Colorectal cancer (CRC) is a major cause of cancer mortality worldwide, however, the molecular mechanisms underlying the pathogenesis of CRC remain largely unclear. Recent studies have revealed crucial roles of transcription factors in CRC development. Transcription factors essential for the regulation of gene expression by interacting with transcription corepressor/enhancer complexes and they orchestrate downstream signal transduction. Deregulation of transcription factors is a frequent occurrence in CRC, and the accompanying drastic changes in gene expression profiles play fundamental roles in multistep process of tumorigenesis, from cellular transformation, disease progression to metastatic disease. Herein, we summarized current and emerging key transcription factors that participate in CRC tumorigenesis, and highlighted their oncogenic or tumor suppressive functions. Moreover, we presented critical transcription factors of CRC, emphasized the major molecular mechanisms underlying their effect on signal cascades associated with tumorigenesis, and summarized of their potential as molecular biomarkers for CRC prognosis therapeutic response, as well as drug targets for CRC treatment. A better understanding of transcription factors involved in the development of CRC will provide new insights into the pathological mechanisms and reveal novel prognostic biomarkers and therapeutic strategies for CRC.
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Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65:87–108.
Sung JJ, Lau JY, Young GP, Sano Y, Chiu HM, Byeon JS, et al. Asia Pacific Working Group on Colorectal, Asia Pacific consensus recommendations for colorectal cancer screening. Gut. 2008;57:1166–76.
Watson IR, Takahashi K, Futreal PA, Chin L. Emerging patterns of somatic mutations in cancer. Nat Rev Genet. 2013;14:703–18.
Fearon ER. Molecular genetics of colorectal cancer. Annu Rev Pathol. 2011;6:479–507.
Shen L, Toyota M, Kondo Y, Lin E, Zhang L, Guo Y, et al. Integrated genetic and epigenetic analysis identifies three different subclasses of colon cancer. Proc Natl Acad Sci USA. 2007;104:18654–9.
Poynter JN, Haile RW, Siegmund KD, Campbell PT, Figueiredo JC, Limburg P, et al. Associations between smoking, alcohol consumption, and colorectal cancer, overall and by tumor microsatellite instability status. Cancer Epidemiol Biomark Prev. 2009;18:2745–50.
Haydon AM, Macinnis RJ, English DR, Giles GG. Effect of physical activity and body size on survival after diagnosis with colorectal cancer. Gut. 2006;55:62–7.
Seymour MT, Maughan TS, Ledermann JA, Topham C, James R, Gwyther SJ, et al. Different strategies of sequential and combination chemotherapy for patients with poor prognosis advanced colorectal cancer (MRC FOCUS): a randomised controlled trial. Lancet. 2007;370:143–52.
Lambert SA, Jolma A, Campitelli LF, Das PK, Yin Y, Albu M, et al. The human transcription factors. Cell. 2018;172:650–65.
Lee TI, Young RA. Transcriptional regulation and its misregulation in disease. Cell. 2013;152:1237–51.
Fitzgerald KA, Evans JC, McCarthy J, Guo J, Prencipe M, Kearney M, et al. The role of transcription factors in prostate cancer and potential for future RNA interference therapy. Expert Opin Ther Targets. 2014;18:633–49.
Konstantinopoulos PA, Papavassiliou AG. Seeing the future of cancer-associated transcription factor drug targets. JAMA. 2011;305:2349–50.
Levy DE, Darnell JE Jr. Stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol. 2002;3:651–62.
Hui K, Yang Y, Shi K, Luo H, Duan J, An J, et al. The p38 MAPK-regulated PKD1/CREB/Bcl-2 pathway contributes to selenite-induced colorectal cancer cell apoptosis in vitro and in vivo. Cancer Lett. 2014;354:189–99.
Rayet B, Gelinas C. Aberrant rel/nfkb genes and activity in human cancer. Oncogene. 1999;18:6938–47.
Yeh JE, Toniolo PA, Frank DA. Targeting transcription factors: promising new strategies for cancer therapy. Curr Opin Oncol. 2013;25:652–8.
Ben-David E, Bester AC, Shifman S, Kerem B. Transcriptional dynamics in colorectal carcinogenesis: new insights into the role of c-Myc and miR17 in benign to cancer transformation. Cancer Res. 2014;74:5532–40.
Xia Y, Shen S, Verma IM. NF-kappaB an active player in human cancers. Cancer Immunol Res. 2014;2:823–30.
Gambhir S, Vyas D, Hollis M, Aekka A, Vyas A. Nuclear factor kappa B role in inflammation associated gastrointestinal malignancies. World J Gastroenterol. 2015;21:3174–83.
Yu LL, Yu HG, Yu JP, Luo HS, Xu XM, Li JH. Nuclear factor-kappaB p65 (RelA) transcription factor is constitutively activated in human colorectal carcinoma tissue. World J Gastroenterol. 2004;10:3255–60.
Liu S, Sun X, Wang M, Hou Y, Zhan Y, Jiang Y, et al. A microRNA 221- and 222-mediated feedback loop maintains constitutive activation of NFkappaB and STAT3 in colorectal cancer cells. Gastroenterology. 2014;147:847–59.
Sakamoto K, Maeda S, Hikiba Y, Nakagawa H, Hayakawa Y, Shibata W, et al. Constitutive NF-kappaB activation in colorectal carcinoma plays a key role in angiogenesis, promoting tumor growth. Clin Cancer Res. 2009;15:2248–58.
Prasad S, Ravindran J, Aggarwal BB. NF-kappaB and cancer: how intimate is this relationship. Mol Cell Biochem. 2010;336:25–37.
Sunami Y, Wirth T. Intestinal carcinogenesis: IKK can go all the way. J Clin Invest. 2011;121:2551–3.
Vaiopoulos AG, Athanasoula K, Papavassiliou AG. NF-kappaB in colorectal cancer. J Mol Med. 2013;91:1029–37.
Greten FR, Eckmann L, Greten TF, Park JM, Li ZW, Egan LJ, et al. IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell. 2004;118:285–96.
Mariani F, Sena P, Roncucci L. Inflammatory pathways in the early steps of colorectal cancer development. World J Gastroenterol. 2014;20:9716–31.
Cooks T, Pateras IS, Tarcic O, Solomon H, Schetter AJ, Wilder S, et al. Mutant p53 prolongs NF-kappaB activation and promotes chronic inflammation and inflammation-associated colorectal cancer. Cancer Cell. 2013;23:634–46.
Buettner R, Mora LB, Jove R. Activated STAT signaling in human tumors provides novel molecular targets for therapeutic intervention. Clin Cancer Res. 2002;8:945–54.
Groner B, von Manstein V. Jak Stat signaling and cancer: opportunities, benefits and side effects of targeted inhibition. Mol Cell Endocrinol. 2017;451:1–14.
Spano JP, Milano G, Rixe C, Fagard R. JAK/STAT signalling pathway in colorectal cancer: a new biological target with therapeutic implications. Eur J Cancer. 2006;42:2668–70.
Yu H, Jove R. The STATs of cancer-new molecular targets come of age. Nat Rev Cancer. 2004;4:97–105.
Bromberg J, Darnell JE Jr. The role of STATs in transcriptional control and their impact on cellular function. Oncogene. 2000;19:2468–73.
Corvinus FM, Orth C, Moriggl R, Tsareva SA, Wagner S, Pfitzner EB, et al. Persistent STAT3 activation in colon cancer is associated with enhanced cell proliferation and tumor growth. Neoplasia. 2005;7:545–55.
Xiong H, Zhang ZG, Tian XQ, Sun DF, Liang QC, Zhang YJ, et al. Inhibition of JAK1, 2/STAT3 signaling induces apoptosis, cell cycle arrest, and reduces tumor cell invasion in colorectal cancer cells. Neoplasia. 2008;10:287–97.
Grivennikov S, Karin E, Terzic J, Mucida D, Yu GY, Vallabhapurapu S, et al. IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell. 2009;15:103–13.
Lin L, Liu A, Peng Z, Lin HJ, Li PK, Li C, et al. STAT3 is necessary for proliferation and survival in colon cancer-initiating cells. Cancer Res. 2011;71:72–7237.
Du W, Wang YC, Hong J, Su WY, Lin YW, Lu R, et al. STAT5 isoforms regulate colorectal cancer cell apoptosis via reduction of mitochondrial membrane potential and generation of reactive oxygen species. J Cell Physiol. 2012;227:2421–9.
Xiong H, Su WY, Liang QC, Zhang ZG, Chen HM, Du W, et al. Inhibition of STAT5 induces G1 cell cycle arrest and reduces tumor cell invasion in human colorectal cancer cells. Lab Invest. 2009;89:717–25.
Hong X, Chen G, Wang M, Lou C, Mao Y, Li Z, et al. STAT5a-targeting miRNA enhances chemosensitivity to cisplatin and 5-fluorouracil in human colorectal cancer cells. Mol Med Rep. 2012;5:1215–9.
Hogan PG, Chen L, Nardone J, Rao A. Transcriptional regulation by calcium, calcineurin, and NFAT. Genes Dev. 2003;17:2205–32.
Daniel C, Gerlach K, Vath M, Neurath MF, Weigmann B. Nuclear factor of activated T cells - a transcription factor family as critical regulator in lung and colon cancer. Int J Cancer. 2014;134:1767–75.
Duque J, Fresno M, Iniguez MA. Expression and function of the nuclear factor of activated T cells in colon carcinoma cells: involvement in the regulation of cyclooxygenase-2. J Biol Chem. 2005;280:8686–93.
Binion DG, Otterson MF, Rafiee P. Curcumin inhibits VEGF-mediated angiogenesis in human intestinal microvascular endothelial cells through COX-2 and MAPK inhibition. Gut. 2008;57:1509–17.
Tripathi MK, Deane NG, Zhu J, An H, Mima S, Wang X, et al. Nuclear factor of activated T-cell activity is associated with metastatic capacity in colon cancer. Cancer Res. 2014;74:6947–57.
Gerlach K, Daniel C, Lehr HA, Nikolaev A, Gerlach T, Atreya R, et al. Transcription factor NFATc2 controls the emergence of colon cancer associated with IL-6-dependent colitis. Cancer Res. 2012;72:4340–50.
Jauliac S, Lopez-Rodriguez C, Shaw LM, Brown LF, Rao A, Toker A. The role of NFAT transcription factors in integrin-mediated carcinoma invasion. Nat Cell Biol. 2002;4:540–4.
Robbs BK, Cruz AL, Werneck MB, Mognol GP, Viola JP. Dual roles for NFAT transcription factor genes as oncogenes and tumor suppressors. Mol Cell Biol. 2008;28:7168–81.
Sakamoto KM, Frank DA. CREB in the pathophysiology of cancer: implications for targeting transcription factors for cancer therapy. Clin Cancer Res. 2009;15:2583–7.
Conkright MD, Montminy M. CREB: the unindicted cancer co-conspirator. Trends Cell Biol. 2005;15:457–9.
Sandoval S, Pigazzi M, Sakamoto KM. CREB: a key regulator of normal and neoplastic hematopoiesis. Adv Hematol. 2009;2009:634292.
Chhabra A, Fernando H, Watkins G, Mansel RE, Jiang WG. Expression of transcription factor CREB1 in human breast cancer and its correlation with prognosis. Oncol Rep. 2007;18:953–8.
Seo HS, Liu DD, Bekele BN, Kim MK, Pisters K, Lippman SM, et al. Cyclic AMP response element-binding protein overexpression: a feature associated with negative prognosis in never smokers with non-small cell lung cancer. Cancer Res. 2008;68:6065–73.
Mayr B, Montminy M. Transcriptional regulation by the phosphorylation-dependent factor CREB. Nat Rev Mol Cell Biol. 2001;2:599–609.
Steven A, Heiduk M, Recktenwald CV, Hiebl B, Wickenhauser C, Massa C, et al. Colorectal carcinogenesis: connecting K-RAS-induced transformation and CREB activity in vitro and in vivo. Mol Cancer Res. 2015;13:1248–62.
Sampurno S, Bijenhof A, Cheasley D, Xu H, Robine S, Hilton D, et al. The Myb-p300-CREB axis modulates intestine homeostasis, radiosensitivity and tumorigenesis. Cell Death Dis. 2013;4:e605.
Xie F, Li BX, Kassenbrock A, Xue C, Wang X, Qian DZ, et al. Identification of a potent inhibitor of CREB-mediated gene transcription with efficacious in vivo anticancer activity. J Med Chem. 2015;58:5075–87.
Shaulian E, Karin M. AP-1 as a regulator of cell life and death. Nat Cell Biol. 2002;4:E131–6.
Kappelmann M, Bosserhoff A, Kuphal S. AP-1/c-Jun transcription factors: regulation and function in malignant melanoma. Eur J Cell Biol. 2014;93:76–81.
Madrigal P, Alasoo K. AP-1 takes centre stage in enhancer chromatin dynamics. Trends Cell Biol. 2018;28:509–11.
Shaulian E, Karin M. AP-1 in cell proliferation and survival. Oncogene. 2001;20:2390–400.
Ashida R, Tominaga K, Sasaki E, Watanabe T, Fujiwara Y, Oshitani N, et al. AP-1 and colorectal cancer. Inflammopharmacology. 2005;13:113–25.
Zhang W, Hart J, McLeod HL, Wang HL. Differential expression of the AP-1 transcription factor family members in human colorectal epithelial and neuroendocrine neoplasms. Am J Clin Pathol. 2005;124:11–9.
Nateri AS, Spencer-Dene B, Behrens A. Interaction of phosphorylated c-Jun with TCF4 regulates intestinal cancer development. Nature. 2005;437:281–5.
Vial E, Sahai E, Marshall CJ. ERK-MAPK signaling coordinately regulates activity of Rac1 and RhoA for tumor cell motility. Cancer Cell. 2003;4:67–79.
Pandey MK, Liu G, Cooper TK, Mulder KM. Knockdown of c-Fos suppresses the growth of human colon carcinoma cells in athymic mice. Int J Cancer. 2012;130:213–22.
Cervantes-Madrid DL, Nagi S, Asting Gustafsson A. FosB transcription factor regulates COX-2 expression in colorectal cancer cells without affecting PGE2 expression. Oncol Lett. 2017;13:1411–6.
Wang F, Ma YL, Zhang P, Shen TY, Shi CZ, Yang YZ, et al. SP1 mediates the link between methylation of the tumour suppressor miR-149 and outcome in colorectal cancer. J Pathol. 2013;229:12–24.
Beishline K, Azizkhan-Clifford J. Sp1 and the ‘hallmarks of cancer’. FEBS J. 2015;282:224–58.
Chang WC, Hung JJ. Functional role of post-translational modifications of Sp1 in tumorigenesis. J Biomed Sci. 2012;19:94.
Jiang W, Jin Z, Zhou F, Cui J, Wang L, Wang L. High co-expression of Sp1 and HER-2 is correlated with poor prognosis of gastric cancer patients. Surg Oncol. 2015;24:220–5.
Shi Q, Le X, Abbruzzese JL, Peng Z, Qian CN, Tang H, et al. Constitutive Sp1 activity is essential for differential constitutive expression of vascular endothelial growth factor in human pancreatic adenocarcinoma. Cancer Res. 2001;61:4143–54.
Hosoi Y, Watanabe T, Nakagawa K, Matsumoto Y, Enomoto A, Morita A, et al. Up-regulation of DNA-dependent protein kinase activity and Sp1 in colorectal cancer. Int J Oncol. 2004;25:461–8.
Zhao Y, Zhang W, Guo Z, Ma F, Wu Y, Bai Y, et al. Inhibition of the transcription factor Sp1 suppresses colon cancer stem cell growth and induces apoptosis in vitro and in nude mouse xenografts. Oncol Rep. 2013;30:1782–92.
Bajpai R, Nagaraju GP. Specificity protein 1: its role in colorectal cancer progression and metastasis. Crit Rev Oncol Hematol. 2017;113:1–7.
Liang H, Zhong Y, Zhou S, Peng L. Knockdown of RAGE expression inhibits colorectal cancer cell invasion and suppresses angiogenesis in vitro and in vivo. Cancer Lett. 2011;313:91–8.
Chen YJ, Chang WM, Liu YW, Lee CY, Jang YH, Kuo CD, et al. A small-molecule metastasis inhibitor, norcantharidin, downregulates matrix metalloproteinase-9 expression by inhibiting Sp1 transcriptional activity in colorectal cancer cells. Chem Biol Interact. 2009;181:440–6.
Kuhajda FP. Fatty-acid synthase and human cancer: new perspectives on its role in tumor biology. Nutrition 2000;16:202–8.
Lu S, Archer MC. Sp1 coordinately regulates de novo lipogenesis and proliferation in cancer cells. Int J Cancer. 2010;126:416–25.
Waby JS, Chirakkal H, Yu C, Griffiths GJ, Benson RS, Bingle CD, et al. Sp1 acetylation is associated with loss of DNA binding at promoters associated with cell cycle arrest and cell death in a colon cell line. Mol Cancer. 2010;9:275.
Chintharlapalli S, Papineni S, Lei P, Pathi S, Safe S. Betulinic acid inhibits colon cancer cell and tumor growth and induces proteasome-dependent and -independent downregulation of specificity proteins (Sp) transcription factors. BMC Cancer. 2011;11:371.
Abdelrahim M, Safe S. Cyclooxygenase-2 inhibitors decrease vascular endothelial growth factor expression in colon cancer cells by enhanced degradation of Sp1 and Sp4 proteins. Mol Pharm. 2005;68:317–29.
Halasi M, Gartel AL. FOX(M1) news-it is cancer. Mol Cancer Ther. 2013;12:245–54.
Wierstra I. FOXM1 (Forkhead box M1) in tumorigenesis: overexpression in human cancer, implication in tumorigenesis, oncogenic functions, tumor-suppressive properties, and target of anticancer therapy. Adv Cancer Res. 2013;119:191–419.
Bella L, Zona S, Nestal de Moraes G, Lam EW. FOXM1: A key oncofoetal transcription factor in health and disease. Semin Cancer Biol. 2014;29:32–9.
Zhang J, Niu Y, Huang C. Role of FoxM1 in the progression and epithelial to mesenchymal transition of gastrointestinal cancer. Recent Pat Anticancer Drug Disco. 2017;12:247–59.
Yoshida Y, Wang IC, Yoder HM, Davidson NO, Costa RH. The forkhead box M1 transcription factor contributes to the development and growth of mouse colorectal cancer. Gastroenterology. 2007;132:1420–31.
Uddin S, Ahmed M, Hussain A, Abubaker J, Al-Sanea N, AbdulJabbar A, et al. Genome-wide expression analysis of Middle Eastern colorectal cancer reveals FOXM1 as a novel target for cancer therapy. Am J Pathol. 2011;178:537–47.
Yue M, Li S, Yan G, Li C, Kang Z. Paeoniflorin inhibits cell growth and induces cell cycle arrest through inhibition of FoxM1 in colorectal cancer cells. Cell Cycle. 2018;17:240–9.
Li D, Wei P, Peng Z, Huang C, Tang H, Jia Z, et al. The critical role of dysregulated FOXM1-PLAUR signaling in human colon cancer progression and metastasis. Clin Cancer Res. 2013;19:62–72.
Lund IK, Illemann M, Thurison T, Christensen IJ, Hoyer-Hansen G. uPAR as anti-cancer target: evaluation of biomarker potential, histological localization, and antibody-based therapy. Curr Drug Targets. 2011;12:1744–60.
Zhang X, Zhang L, Du Y, Zheng H, Zhang P, Sun Y, et al. A novel FOXM1 isoform, FOXM1D, promotes epithelial-mesenchymal transition and metastasis through ROCKs activation in colorectal cancer. Oncogene 2017;36:807–19.
Jin H, Li XJ, Park MH, Kim SM. FOXM1-mediated downregulation of uPA and MMP9 by 3,3’-diindolylmethane inhibits migration and invasion of human colorectal cancer cells. Oncol Rep. 2015;33:3171–7.
Yang K, Jiang L, Hu Y, Yu J, Chen H, Yao Y, et al. Short hairpin RNA- mediated gene knockdown of FOXM1 inhibits the proliferation and metastasis of human colon cancer cells through reversal of epithelial-to-mesenchymal transformation. J Exp Clin Cancer Res. 2015;34:40.
Song IS, Jeong YJ, Jeong SH, Heo HJ, Kim HK, Bae KB, et al. FOXM1-induced PRX3 regulates stemness and survival of colon cancer cells via maintenance of mitochondrial function. Gastroenterology 2015;149:1006–16.
Ahmed M, Hussain AR, Siraj AK, Uddin S, Al-Sanea N, Al-Dayel F, et al. Co-targeting of Cyclooxygenase-2 and FoxM1 is a viable strategy in inducing anticancer effects in colorectal cancer cells. Mol Cancer. 2015;14:131.
Wade M, Li YC, Wahl GM. MDM2, MDMX and p53 in oncogenesis and cancer therapy. Nat Rev Cancer. 2013;13:83–96.
Takayama T, Miyanishi K, Hayashi T, Sato Y, Niitsu Y. Colorectal cancer: genetics of development and metastasis. J Gastroenterol. 2006;41:185–92.
Iacopetta B. TP53 mutation in colorectal cancer. Hum Mut. 2003;21:271–6.
Tortola S, Marcuello E, Gonzalez I, Reyes G, Arribas R, Aiza G, et al. p53 and K-ras gene mutations correlate with tumor aggressiveness but are not of routine prognostic value in colorectal cancer. J Clin Oncol. 1999;17:1375–81.
Roger L, Jullien L, Gire V, Roux P. Gain of oncogenic function of p53 mutants regulates E-cadherin expression uncoupled from cell invasion in colon cancer cells. J Cell Sci. 2010;123:1295–305.
Stein Y, Rotter V, Aloni-Grinstein R. Gain-of-function Mutant p53: all the roads lead to tumorigenesis. Int J Mol Sci. 2019;20:6197.
Weisz L, Damalas A, Liontos M, Karakaidos P, Fontemaggi G, Maor-Aloni R, et al. Mutant p53 enhances nuclear factor kappaB activation by tumor necrosis factor alpha in cancer cells. Cancer Res. 2007;67:2396–401.
Schulz-Heddergott R, Stark N, Edmunds SJ, Li J, Conradi LC, Bohnenberger H, et al. Therapeutic ablation of gain-of-function mutant p53 in colorectal cancer inhibits Stat3-mediated tumor growth and invasion. Cancer Cell. 2018;34:298–314.
Liu Y, Ao X, Ding W, Ponnusamy M, Wu W, Hao X, et al. Critical role of FOXO3a in carcinogenesis. Mol Cancer. 2018;17:104.
Bullock MD, Bruce A, Sreekumar R, Curtis N, Cheung T, Reading I, et al. FOXO3 expression during colorectal cancer progression: biomarker potential reflects a tumour suppressor role. Br J cancer. 2013;109:387–94.
Wang X, Hu S, Liu L. Phosphorylation and acetylation modifications of FOXO3a: Independently or synergistically? Oncol Lett. 2017;13:2867–72.
Yang JY, Zong CS, Xia W, Yamaguchi H, Ding Q, Xie X, et al. ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation. Nat Cell Biol. 2008;10:138–48.
Hu MC, Lee DF, Xia W, Golfman LS, Ou-Yang F, Yang JY, et al. IkappaB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a. Cell. 2004;117:225–37.
Grevenynghe JV, Cubas RA, DaFonseca S, Metcalf T, Tremblay CL, Trautmann L, et al. Foxo3a: an integrator of immune dysfunction during HIV infection. Cytokine Growth Factor Rev. 2012;23:215–21.
Shoeb M, Ramana KV, Srivastava SK. Aldose reductase inhibition enhances TRAIL-induced human colon cancer cell apoptosis through AKT/FOXO3a-dependent upregulation of death receptors. Free Rad Biol. Med. 2013;63:280–90.
Kops GJ, Dansen TB, Polderman PE, Saarloos I, Wirtz KW, Coffer PJ, et al. Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress. Nature. 2002;419:316–21.
Fernandez de Mattos S, Villalonga P, Clardy J, Lam EW. FOXO3a mediates the cytotoxic effects of cisplatin in colon cancer cells. Mol Cancer Ther. 2008;7:3237–46.
Germani A, Matrone A, Grossi V, Peserico A, Sanese P, Liuzzi M, et al. Targeted therapy against chemoresistant colorectal cancers: Inhibition of p38α modulates the effect of cisplatin in vitro and in vivo through the tumor suppressor FoxO3A. Cancer Lett. 2014;344:110–8.
Qi W, Weber CR, Wasland K, Savkovic SD. Genistein inhibits proliferation of colon cancer cells by attenuating a negative effect of epidermal growth factor on tumor suppressor FOXO3 activity. BMC Cancer. 2011;11:219.
Luo H, Yang Y, Duan J, Wu P, Jiang Q, Xu C. PTEN-regulated AKT/FoxO3a/ Bim signaling contributes to reactive oxygen species-mediated apoptosis in selenite-treated colorectal cancer cells. Cell Death Dis. 2014;4:e481.
Qazi AK, Hussain A, Khan S, Aga MA, Behl A, Ali S, et al. Quinazoline based small molecule exerts potent tumour suppressive properties by inhibiting PI3K/Akt/ FoxO3a signalling in experimental colon cancer. Cancer Lett. 2015;359:47–56.
Marzi L, Combes E, Vie N, Ayrolles-Torro A, Tosi D, Desigaud D, et al. FOXO3a and the MAPK p38 are activated by cetuximab to induce cell death and inhibit cell proliferation and their expression predicts cetuximab efficacy in colorectal cancer. Br J Cancer. 2016;115:1223–33.
Tenbaum SP, Ordonez-Moran P, Puig I, Chicote I, Arques O, Landolfi S, et al. Beta-catenin confers resistance to PI3K and AKT inhibitors and subverts FOXO3a to promote metastasis in colon cancer. Nat Med. 2012;18:892–901.
Arques O, Chicote I, Puig I, Tenbaum SP, Argiles G, Dienstmann R, et al. Tankyrase inhibition blocks Wnt/beta-catenin pathway and reverts resistance to PI3K and AKT inhibitors in the treatment of colorectal cancer. Clini Cancer Res. 2016;22:644–56.
Khaleghpour K, Li Y, Banville D, Yu Z, Shen SH. Involvement of the PI 3-kinase signaling pathway in progression of colon adenocarcinoma. Carcinogenesis. 2004;25:241–8.
Itoh N, Semba S, Ito M, Takeda H, Kawata S, Yamakawa M. Phosphorylation of Akt/PKB is required for suppression of cancer cell apoptosis and tumor progression in human colorectal carcinoma. Cancer. 2002;94:3127–34.
Qi W, Weber CR, Wasland K, Roy H, Wali R, Joshi S, et al. Tumor suppressor FOXO3 mediates signals from the EGF receptor to regulate proliferation of colonic cells. Am J Physiol. 2011;300:G264–72.
Dehner M, Hadjihannas M, Weiske J, Huber O, Behrens J. Wnt signaling inhibits Forkhead box O3a-induced transcription and apoptosis through up-regulation of serum- and glucocorticoid-inducible kinase 1. J Biol Chem. 2008;283:19201–10.
Sarkar M, Khare V, Guturi KK, Das N, Ghosh MK. The DEAD box protein p68: a crucial regulator of AKT/FOXO3a signaling axis in oncogenesis. Oncogene. 2015;34:5843–56.
Song KH, Woo SR, Chung JY, Lee HJ, Oh SJ, Hong SO, et al. REP1 inhibits FOXO3-mediated apoptosis to promote cancer cell survival. Cell Death Dis. 2017;8:e2536.
Mishra L, Shetty K, Tang Y, Stuart A, Byers SW. The role of TGF-beta and Wnt signaling in gastrointestinal stem cells and cancer. Oncogene. 2005;24:5775–89.
Subramaniam MM, Chan JY, Yeoh KG, Quek T, Ito K, Salto-Tellez M. Molecular pathology of RUNX3 in human carcinogenesis. Biochim Biophys Acta. 2009;1796:315–31.
Chen F, Liu X, Bai J, Pei D, Zheng J. The emerging role of RUNX3 in cancer metastasis. Oncol Rep. 2016;35:1227–36.
Goel A, Arnold CN, Tassone P, Chang DK, Niedzwiecki D, Dowell JM, et al. Epigenetic inactivation of RUNX3 in microsatellite unstable sporadic colon cancers. Int J Cancer. 2004;112:754–9.
Imamura Y, Hibi K, Koike M, Fujiwara M, Kodera Y, Ito K, et al. RUNX3 promoter region is specifically methylated in poorly-differentiated colorectal cancer. Anticancer Res. 2005;25:2627–30.
Ku JL, Kang SB, Shin YK, Kang HC, Hong SH, Kim IJ, et al. Promoter hypermethylation downregulates RUNX3 gene expression in colorectal cancer cell lines. Oncogene. 2004;23:6736–42.
Subramaniam MM, Chan JY, Soong R, Ito K, Yeoh KG, Wong R, et al. RUNX3 inactivation in colorectal polyps arising through different pathways of colonic carcinogenesis. Am J Gastroenterol. 2009;104:426–36.
Kodach LL, Jacobs RJ, Heijmans J, Noesel CJ, Langers AM, Verspaget HW, et al. The role of EZH2 and DNA methylation in the silencing of the tumour suppressor RUNX3 in colorectal cancer. Carcinogenesis. 2010;31:1567–75.
Ito K, Lim AC, Salto-Tellez M, Motoda L, Osato M, Chuang LS, et al. RUNX3 attenuates beta-catenin/T cell factors in intestinal tumorigenesis. Cancer Cell. 2008;14:226–37.
Lee CW, Ito K, Ito Y. Role of RUNX3 in bone morphogenetic protein signaling in colorectal cancer. Cancer Res. 2010;70:4243–52.
Zhao W, Hisamuddin IM, Nandan MO, Babbin BA, Lamb NE, Yang VW. Identification of Kruppel-like factor 4 as a potential tumor suppressor gene in colorectal cancer. Oncogene. 2004;23:395–402.
Xu J, Lu B, Xu F, Gu H, Fang Y, Huang Q, et al. Dynamic down-regulation of Kruppel-like factor 4 in colorectal adenoma-carcinoma sequence. J Cancer Res Clin Oncol. 2008;134:891–8.
Dang DT, Bachman KE, Mahatan CS, Dang LH, Giardiello FM, Yang VW. Decreased expression of the gut-enriched Kruppel-like factor gene in intestinal adenomas of multiple intestinal neoplasia mice and in colonic adenomas of familial adenomatous polyposis patients. FEBS Lett. 2000;476:203–7.
Dang DT, Chen X, Feng J, Torbenson M, Dang LH, Yang VW. Overexpression of Kruppel-like factor 4 in the human colon cancer cell line RKO leads to reduced tumorigenecity. Oncogene. 2003;22:3424–30.
Chen X, Johns DC, Geiman DE, Marban E, Dang DT, Hamlin G, et al. Kruppel-like factor 4 (gut-enriched Kruppel-like factor) inhibits cell proliferation by blocking G1/S progression of the cell cycle. J Biol Chem. 2001;276:30423–8.
Ghaleb AM, Elkarim EA, Bialkowska AB, Yang VW. KLF4 suppresses tumor formation in genetic and pharmacological mouse models of colonic tumorigenesis. Mol Cancer Res. 2016;14:385–96.
Zhang W, Chen X, Kato Y, Evans PM, Yuan S, Yang J, et al. Novel cross talk of Kruppel-like factor 4 and beta-catenin regulates normal intestinal homeostasis and tumor repression. Mol Cell Biol. 2006;26:2055–64.
Yang VW, Liu Y, Kim J, Shroyer KR, Bialkowska AB. Increased genetic instability and accelerated progression of colitis-associated colorectal cancer through intestinal epithelium-specific deletion of Klf4. Mol Cancer Res. 2019;17:165–76.
Okugawa Y, Grady WM, Goel A. Epigenetic alterations in colorectal cancer: emerging biomarkers. Gastroenterology 2015;149:1204–25.
Zhou X, Shan Z, Yang H, Xu J, Li W, Guo F. RelB plays an oncogenic role and conveys chemo-resistance to DLD-1 colon cancer cells. Cancer Cell Int. 2018;18:181.
Patel M, Horgan PG, McMillan DC, Edwards J. NF-kappaB pathways in the development and progression of colorectal cancer. Transl Res. 2018;197:43–56.
Lagadec P, Griessinger E, Nawrot MP, Fenouille N, Colosetti P, Imbert V, et al. Pharmacological targeting of NF-kappaB potentiates the effect of the topoisomerase inhibitor CPT-11 on colon cancer cells. Br J Cancer. 2008;98:335–44.
Sakai E, Fukuyo M, Matsusaka K, Ohata K, Doi N, Takane K, et al. TP53 mutation at early stage of colorectal cancer progression from two types of laterally spreading tumors. Cancer Sci. 2016;107:820–7.
Russo A, Bazan V, Iacopetta B, Kerr D, Soussi T, Gebbia N. The TP53 colorectal cancer international collaborative study on the prognostic and predictive significance of p53 mutation: influence of tumor site, type of mutation, and adjuvant treatment. J Clin Oncol. 2005;23:7518–28.
Iacopetta B, Russo A, Bazan V, Dardanoni G, Gebbia N, Soussi T, et al. Functional categories of TP53 mutation in colorectal cancer: results of an International Collaborative Study. Ann Oncol. 2006;17:842–7.
Li XL, Zhou J, Chen ZR, Chng WJ. P53 mutations in colorectal cancer-molecular pathogenesis and pharmacological reactivation. World J Gastroenterol. 2015;21:84–93.
Ogino S, Meyerhardt JA, Kawasaki T, Clark JW, Ryan DR, Kulke MH, et al. CpG island methylation, response to combination chemotherapy, and patient survival in advanced microsatellite stable colorectal carcinoma. Virchows Arch. 2007;450:529–37.
Soong R, Shah N, Peh BK, Chong PY, Ng SS, Zeps N, et al. The expression of RUNX3 in colorectal cancer is associated with disease stage and patient outcome. Br J Cancer. 2009;100:676–9.
Patel NV, Ghaleb AM, Nandan MO, Yang VW. Expression of the tumor suppressor Kruppel-like factor 4 as a prognostic predictor for colon cancer. Cancer Epidemiol Biomark Prev. 2010;19:2631–8.
Kunnumakkara AB, Guha S, Krishnan S, Diagaradjane P, Gelovani J, Aggarwal BB. Curcumin potentiates antitumor activity of gemcitabine in an orthotopic model of pancreatic cancer through suppression of proliferation, angiogenesis, and inhibition of nuclear factor-kappaB-regulated gene products. Cancer Res. 2007;67:3853–61.
Rajitha B, Belalcazar A, Nagaraju GP, Shaib WL, Snyder JP, Shoji M, et al. Inhibition of NF-kappaB translocation by curcumin analogs induces G0/G1 arrest and downregulates thymidylate synthase in colorectal cancer. Cancer Lett. 2016;373:227–33.
Schaffer M, Schaffer PM, Bar-Sela G. An update on Curcuma as a functional food in the control of cancer and inflammation. Curr Opin Clin Nutr Metab Care. 2015;18:605–11.
Cruz-Correa M, Hylind LM, Marrero JH, Zahurak ML, Murray-Stewart T, Casero RA, et al. Efficacy and safety of curcumin in treatment of intestinal adenomas in patients with familial adenomatous polyposis. Gastroenterology 2018;155:668–73.
Kane RC, Bross PF, Farrell AT, Pazdur R. Velcade: U.S. FDA approval for the treatment of multiple myeloma progressing on prior therapy. Oncologist. 2003;8:508–13.
Dunleavy K, Pittaluga S, Czuczman MS, Dave SS, Wright G, Grant N, et al. Differential efficacy of bortezomib plus chemotherapy within molecular subtypes of diffuse large B-cell lymphoma. Blood. 2009;113:6069–76.
Furqan M, Akinleye A, Mukhi N, Mittal V, Chen Y, Liu D. STAT inhibitors for cancer therapy. J Hematol Oncol. 2013;6:90.
Page BD, Ball DP, Gunning PT. Signal transducer and activator of transcription 3 inhibitors: a patent review. Expert Opin Ther Pat. 2011;21:65–83.
Lai PS, Rosa DA, Magdy Ali A, Gomez-Biagi RF, Ball DP, Shouksmith AE, et al. A STAT inhibitor patent review: progress since 2011. Expert Opin Ther Pat. 2015;25:1397–421.
Hubbard JM, Grothey A. Napabucasin: an update on the first-in-class cancer stemness inhibitor. Drugs. 2017;77:1091–103.
Yu H, Kortylewski M, Pardoll D. Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment. Nat Rev Immunol. 2007;7:41–51.
Wang D, Yu W, Lian J, Wu Q, Liu S, Yang L, et al. Th17 cells inhibit CD8(+) T cell migration by systematically downregulating CXCR3 expression via IL-17A/STAT3 in advanced-stage colorectal cancer patients. J Hematol Oncol. 2020;13:68.
Shen H, Maki CG. Pharmacologic activation of p53 by small-molecule MDM2 antagonists. Curr Pharm Des. 2011;17:560–8.
Demir S, Boldrin E, Sun Q, Hampp S, Tausch E, Eckert C, et al. Therapeutic targeting of mutant p53 in pediatric acute lymphoblastic leukemia. Haematologica. 2020;105:170–81.
Nagarsheth N, Peng D, Kryczek I, Wu K, Li W, Zhao E, et al. PRC2 epigenetically silences Th1-type chemokines to suppress effector T-cell trafficking in colon cancer. Cancer Res. 2016;76:275–82.
This project was supported by the Natural Science Foundation of China (81802331, 81772501), Research Grants Council-General Research Fund (RGC-GRF; 14101917, 14108718, 14163817 and 14110819), Hong Kong; Heath and Medical Research Fund (HMRF) (06170686).
Conflict of interest
The authors declare that they have no conflict of interest.
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The original online version of this article was revised: Unfortunately, the initially published version did not point out that Hui Xu and Lei Liu are equal contributors.
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Xu, H., Liu, L., Li, W. et al. Transcription factors in colorectal cancer: molecular mechanism and therapeutic implications. Oncogene 40, 1555–1569 (2021). https://doi.org/10.1038/s41388-020-01587-3
International Journal of Molecular Sciences (2021)