The PRC2 and PRC1 complexes are aberrantly expressed in human cancers and have been linked to decreases in patient survival. MUC1-C is an oncoprotein that is also overexpressed in diverse human cancers and is associated with a poor prognosis. Recent studies have supported a previously unreported function for MUC1-C in activating PRC2 and PRC1 in cancer cells. In the regulation of PRC2, MUC1-C (i) drives transcription of the EZH2 gene, (ii) binds directly to EZH2, and (iii) enhances occupancy of EZH2 on target gene promoters with an increase in H3K27 trimethylation. Regarding PRC1, which is recruited to PRC2 sites in the hierarchical model, MUC1-C induces BMI1 transcription, forms a complex with BMI1, and promotes H2A ubiquitylation. MUC1-C thereby contributes to the integration of PRC2 and PRC1-mediated repression of tumor suppressor genes, such as CDH1, CDKN2A, PTEN and BRCA1. Like PRC2 and PRC1, MUC1-C is associated with the epithelial-mesenchymal transition (EMT) program, cancer stem cell (CSC) state, and acquisition of anticancer drug resistance. In concert with these observations, targeting MUC1-C downregulates EZH2 and BMI1, inhibits EMT and the CSC state, and reverses drug resistance. These findings emphasize the significance of MUC1-C as a therapeutic target for inhibiting aberrant PRC function and reprogramming the epigenome in human cancers.
Subscribe to Journal
Get full journal access for 1 year
only $9.98 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Sparmann A, van Lohuizen M. Polycomb silencers control cell fate, development and cancer. Nat Rev Cancer. 2006;6:846–56.
Bracken AP, Helin K. Polycomb group proteins: navigators of lineage pathways led astray in cancer. Nat Rev Cancer. 2009;9:773–84.
Koppens M, van Lohuizen M. Context-dependent actions of Polycomb repressors in cancer. Oncogene 2016;35:1341–52.
Blackledge NP, Rose NR, Klose RJ. Targeting Polycomb systems to regulate gene expression: modifications to a complex story. Nat Rev Mol Cell Biol. 2015;16:643–9.
Riising EM, Comet I, Leblanc B, Wu X, Johansen JV, Helin K. Gene silencing triggers Polycomb Repressive Complex 2 recruitment to CpG islands genome wide. Mol Cell. 2014;55:347–60.
Mills AA. Throwing the cancer switch: reciprocal roles of polycomb and trithorax proteins. Nat Rev Cancer. 2010;10:669–82.
Comet I, Riising EM, Leblanc B, Helin K. Maintaining cell identity: PRC2-mediated regulation of transcription and cancer. Nat Rev Cancer. 2016;16:803–10.
Siddique HR, Saleem M. Role of BMI1, a stem cell factor, in cancer recurrence and chemoresistance: preclinical and clinical evidences. Stem Cells. 2012;30:372–8.
Wang H, Wang L, Erdjument-Bromage H, Vidal M, Tempst P, Jones RS, et al. Role of histone H2A ubiquitination in Polycomb silencing. Nature 2004;431:873–8.
Cao R, Tsukada Y, Zhang Y. Role of Bmi-1 and Ring1A in H2A ubiquitylation and Hox gene silencing. Mol Cell. 2005;20:845–54.
Vire E, Brenner C, Deplus R, Blanchon L, Fraga M, Didelot C, et al. The Polycomb group protein EZH2 directly controls DNA methylation. Nature 2006;439:871–4.
Schlesinger Y, Straussman R, Keshet I, Farkash S, Hecht M, Zimmerman J, et al. Polycomb-mediated methylation on Lys27 of histone H3 pre-marks genes for de novo methylation in cancer. Nat Genet. 2007;39:232–6.
Cedar H, Bergman Y. Linking DNA methylation and histone modification: patterns and paradigms. Nat Rev Genet. 2009;10:295–304.
Bracken AP, Pasini D, Capra M, Prosperini E, Colli E, Helin K. EZH2 is downstream of the pRB-E2F pathway, essential for proliferation and amplified in cancer. EMBO J. 2003;22:5323–35.
Gong Y, Huo L, Liu P, Sneige N, Sun X, Ueno NT, et al. Polycomb group protein EZH2 is frequently expressed in inflammatory breast cancer and is predictive of worse clinical outcome. Cancer 2011;117:5476–84.
Collett K, Eide GE, Arnes J, Stefansson IM, Eide J, Braaten A, et al. Expression of enhancer of zeste homologue 2 is significantly associated with increased tumor cell proliferation and is a marker of aggressive breast cancer. Clin Cancer Res. 2006;12:1168–74.
Kleer CG, Cao Q, Varambally S, Shen R, Ota I, Tomlins SA, et al. EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc Natl Acad Sci USA. 2003;100:11606–11.
Jang SH, Lee JE, Oh MH, Lee JH, Cho HD, Kim KJ, et al. High EZH2 protein expression is associated with poor overall survival in patients with luminal A breast cancer. J Breast Cancer. 2016;19:53–60.
Inari H, Suganuma N, Kawachi K, Yoshida T, Yamanaka T, Nakamura Y, et al. Expression of enhancer of zeste homolog 2 correlates with survival outcome in patients with metastatic breast cancer: exploratory study using primary and paired metastatic lesions. BMC Cancer. 2017;17:160.
Sauvageau M, Sauvageau G. Polycomb group proteins: multi-faceted regulators of somatic stem cells and cancer. Cell Stem Cell. 2010;7:299–313.
Behrens C, Solis LM, Lin H, Yuan P, Tang X, Kadara H, et al. EZH2 protein expression associates with the early pathogenesis, tumor progression, and prognosis of non-small cell lung carcinoma. Clin Cancer Res. 2013;19:6556–65.
Sato T, Kaneda A, Tsuji S, Isagawa T, Yamamoto S, Fujita T, et al. PRC2 overexpression and PRC2-target gene repression relating to poorer prognosis in small cell lung cancer. Sci Rep. 2013;3:1911.
Wang X, Zhao H, Lv L, Bao L, Wang X, Han S. Prognostic significance of EZH2 expression in non-small cell lung cancer: A meta-analysis. Sci Rep. 2016;6:19239.
Varambally S, Dhanasekaran SM, Zhou M, Barrette TR, Kumar-Sinha C, Sanda MG, et al. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 2002;419:624–9.
Chen S, Huang L, Sun K, Wu D, Li M, Li M, et al. Enhancer of zeste homolog 2 as an independent prognostic marker for cancer: a meta-analysis. PLoS ONE. 2015;10:e0125480.
Kim KH, Roberts CW. Targeting EZH2 in cancer. Nat Med. 2016;22:128–34.
Wang Y, Zhe H, Ding Z, Gao P, Zhang N, Li G. Cancer stem cell marker Bmi-1 expression is associated with basal-like phenotype and poor survival in breast cancer. World J Surg. 2012;36:1189–94.
Crea F, Paolicchi E, Marquez VE, Danesi R. Polycomb genes and cancer: time for clinical application? Crit Rev Oncol Hematol. 2012;83:184–93.
Vrzalikova K, Skarda J, Ehrmann J, Murray PG, Fridman E, Kopolovic J, et al. Prognostic value of Bmi-1 oncoprotein expression in NSCLC patients: a tissue microarray study. J Cancer Res Clin Oncol. 2008;134:1037–42.
Glinsky GV, Berezovska O, Glinskii AB. Microarray analysis identifies a death-from-cancer signature predicting therapy failure in patients with multiple types of cancer. J Clin Invest. 2005;115:1503–21.
Yan KS, Lin CY, Liao TW, Peng CM, Lee SC, Liu YJ et al. EZH2 in cancer progression and potential application in cancer therapy: a friend or foe? Int J Mol Sci. 2017;18:E1172.
Kreso A, van Galen P, Pedley NM, Lima-Fernandes E, Frelin C, Davis T, et al. Self-renewal as a therapeutic target in human colorectal cancer. Nat Med. 2014;20:29–36.
Yong KJ, Basseres DS, Welner RS, Zhang WC, Yang H, Yan B, et al. Targeted BMI1 inhibition impairs tumor growth in lung adenocarcinomas with low CEBPalpha expression. Sci Transl Med. 2016;8:350ra104.
Huang R, Cheung NK, Vider J, Cheung IY, Gerald WL, Tickoo SK, et al. MYCN and MYC regulate tumor proliferation and tumorigenesis directly through BMI1 in human neuroblastomas. FASEB J. 2011;25:4138–49.
Rajabi H, Hiraki M, Tagde A, Alam M, Bouillez A, Christensen CL et al. MUC1-C activates EZH2 expression and function in human cancer cells. Sci Rep. 2017;7:7481.
Hiraki M, Maeda T, Bouillez A, Alam M, Tagde A, Hinohara K et al. MUC1-C activates BMI1 in human cancer cells. Oncogene 2016;36:2791–801.
Kufe D. Mucins in cancer: function, prognosis and therapy. Nat Rev Cancer. 2009;9:874–85.
Duraisamy S, Kufe T, Ramasamy S, Kufe D. Evolution of the human MUC1 oncoprotein. Int. J Oncol. 2007;31:671–7.
Kufe D. MUC1-C oncoprotein as a target in breast cancer: activation of signaling pathways and therapeutic approaches. Oncogene 2013;32:1073–81.
Li Y, Liu D, Chen D, Kharbanda S, Kufe D. Human DF3/MUC1 carcinoma-associated protein functions as an oncogene. Oncogene 2003;22:6107–10.
Rajabi H, Kufe D. MUC1-C oncoprotein integrates a program of EMT, epigenetic reprogramming and immune evasion in human carcinomas. BBA Rev Cancer. 2017;1868:117–22.
Li Y, Ren J, Yu W, Li G, Kuwahara H, Yin L, et al. The EGF receptor regulates interaction of the human DF3/MUC1 carcinoma antigen with c-Src and β-catenin. J Biol Chem. 2001;276:35239–42.
Ramasamy S, Duraisamy S, Barbashov S, Kawano T, Kharbanda S, Kufe D. The MUC1 and galectin-3 oncoproteins function in a microRNA-dependent regulatory loop. Mol Cell. 2007;27:992–1004.
Ren J, Raina D, Chen W, Li G, Huang L, Kufe D. MUC1 oncoprotein functions in activation of fibroblast growth factor receptor signaling. Mol Cancer Res. 2006;4:873–83.
Singh PK, Wen Y, Swanson BJ, Shanmugam K, Kazlauskas A, Cerny RL, et al. Platelet-derived growth factor receptor beta-mediated phosphorylation of MUC1 enhances invasiveness in pancreatic adenocarcinoma cells. Cancer Res. 2007;67:5201–10.
Singh PK, Behrens ME, Eggers JP, Cerny RL, Bailey JM, Shanmugam K, et al. Phosphorylation of MUC1 by Met modulates interaction with p53 and MMP1 expression. J Biol Chem. 2008;283:26985–95.
Raina D, Uchida Y, Kharbanda A, Rajabi H, Panchamoorthy G, Jin C, et al. Targeting the MUC1-C oncoprotein downregulates HER2 activation and abrogates trastuzumab resistance in breast cancer cells. Oncogene 2014;33:3422–31.
Kosugi M, Ahmad R, Alam M, Uchida Y, Kufe D. MUC1-C oncoprotein regulates glycolysis and pyruvate kinase M2 activity in cancer cells. PLoS ONE. 2011;6:e28234.
Yin L, Kosugi M, Kufe D. Inhibition of the MUC1-C oncoprotein induces multiple myeloma cell death by downregulating TIGAR expression and depleting NADPH. Blood 2012;119:810–6.
Ahmad R, Alam M, Hasegawa M, Uchida Y, Al-Obaid O, Kharbanda S, et al. Targeting MUC1-C inhibits the AKT-S6K1-elF4A pathway regulating TIGAR translation in colorectal cancer. Mol Cancer. 2017;16:33.
Gunda V, Souchek J, Abrego J, Shukla SK, Goode GD, Vernucci E et al. MUC1-mediated metabolic alterations regulate response to radiotherapy in pancreatic cancer. Clin Cancer Res. 2017;23:5881–91.
Hasegawa M, Takahashi H, Rajabi H, Alam M, Suzuki Y, Yin L, et al. Functional interactions of the cystine/glutamate antiporter, CD44v and MUC1-C oncoprotein in triple-negative breast cancer cells. Oncotarget 2016;7:11756–69.
Goode G, Gunda V, Chaika NV, Purohit V, Yu F, Singh PK. MUC1 facilitates metabolomic reprogramming in triple-negative breast cancer. PLoS ONE. 2017;12:e0176820.
Leng Y, Cao C, Ren J, Huang L, Chen D, Ito M, et al. Nuclear import of the MUC1-C oncoprotein is mediated by nucleoporin Nup62. J Biol Chem. 2007;282:19321–30.
Yamamoto M, Bharti A, Li Y, Kufe D. Interaction of the DF3/MUC1 breast carcinoma-associated antigen and β-catenin in cell adhesion. J Biol Chem. 1997;272:12492–4.
Rajabi H, Ahmad R, Jin C, Kosugi M, Alam M, Joshi M, et al. MUC1-C oncoprotein induces TCF7L2 transcription factor activation and promotes cyclin D1 expression in human breast cancer cells. J Biol Chem. 2012;287:10703–13.
Wei X, Xu H, Kufe D. Human MUC1 oncoprotein regulates p53-responsive gene transcription in the genotoxic stress response. Cancer Cell. 2005;7:167–78.
Ahmad R, Raina D, Joshi MD, Kawano T, Kharbanda S, Kufe D. MUC1-C oncoprotein functions as a direct activator of the NF-κB p65 transcription factor. Cancer Res. 2009;69:7013–21.
Khodarev N, Ahmad R, Rajabi H, Pitroda S, Kufe T, McClary C, et al. Cooperativity of the MUC1 oncoprotein and STAT1 pathway in poor prognosis human breast cancer. Oncogene 2010;29:920–9.
Ahmad R, Rajabi H, Kosugi M, Joshi M, Alam M, Vasir B, et al. MUC1-C oncoprotein promotes STAT3 activation in an auto-inductive regulatory loop. Sci Signal. 2011;4:ra9.
Chaika NV, Gebregiworgis T, Lewallen ME, Purohit V, Radhakrishnan P, Liu X, et al. MUC1 mucin stabilizes and activates hypoxia-inducible factor 1 alpha to regulate metabolism in pancreatic cancer. Proc Natl Acad Sci USA. 2012;109:13787–92.
Shukla SK, Purohit V, Mehla K, Gunda V, Chaika NV, Vernucci E, et al. MUC1 and HIF-1alpha signaling crosstalk induces anabolic glucose metabolism to impart gemcitabine resistance to pancreatic cancer. Cancer Cell. 2017;32:71–87. e77
Khodarev N, Pitroda S, Beckett M, MacDermed D, Huang L, Kufe D, et al. MUC1-induced transcriptional programs associated with tumorigenesis predict outcome in breast and lung cancer. Cancer Res. 2009;69:2833–7.
MacDermed DM, Khodarev NN, Pitroda SP, Edwards DC, Pelizzari CA, Huang L, et al. MUC1-associated proliferation signature predicts outcomes in lung adenocarcinoma patients. BMC Med Genom. 2010;3:16.
Pitroda S, Khodarev N, Beckett M, Kufe D, Weichselbaum R. MUC1-induced alterations in a lipid metabolic gene network predict response of human breast cancers to tamoxifen treatment. Proc Natl Acad Sci USA. 2009;106:5837–41.
Takahashi H, Jin C, Rajabi H, Pitroda S, Alam M, Ahmad R, et al. MUC1-C activates the TAK1 inflammatory pathway in colon cancer. Oncogene 2015;34:5187–97.
Ahmad R, Raina D, Trivedi V, Ren J, Rajabi H, Kharbanda S, et al. MUC1 oncoprotein activates the IκB kinase β complex and constitutive NF-κB signaling. Nat Cell Biol. 2007;9:1419–27.
Rajabi H, Alam M, Takahashi H, Kharbanda A, Guha M, Ahmad R, et al. MUC1-C oncoprotein activates the ZEB1/miR-200c regulatory loop and epithelial-mesenchymal transition. Oncogene 2014;33:1680–9.
Bouillez A, Rajabi H, Pitroda S, Jin C, Alam M, Kharbanda A, et al. Inhibition of MUC1-C suppresses MYC expression and attenuates malignant growth in KRAS mutant lung adenocarcinomas. Cancer Res. 2016;76:1538–48.
Min J, Zaslavsky A, Fedele G, McLaughlin SK, Reczek EE, De Raedt T. et al. An oncogene-tumor suppressor cascade drives metastatic prostate cancer by coordinately activating Ras and nuclear factor-kappaB. Nat Med. 2010;16: 286–94.
Chang CJ, Yang JY, Xia W, Chen CT, Xie X, Chao CH, et al. EZH2 promotes expansion of breast tumor initiating cells through activation of RAF1-beta-catenin signaling. Cancer Cell. 2011;19:86–100.
Puppe J, Drost R, Liu X, Joosse SA, Evers B, Cornelissen-Steijger P, et al. BRCA1-deficient mammary tumor cells are dependent on EZH2 expression and sensitive to Polycomb Repressive Complex 2-inhibitor 3-deazaneplanocin A. Breast Cancer Res. 2009;11:R63.
Li Y, Bharti A, Chen D, Gong J, Kufe D. Interaction of glycogen synthase kinase 3β with the DF3/MUC1 carcinoma-associated antigen and β-catenin. Mol Cell Biol. 1998;18:7216–24.
Tagde A, Rajabi H, Bouillez A, Alam M, Gali R, Bailey S, et al. MUC1-C drives MYC in multiple myeloma. Blood 2016;127:2587–97.
Tagde A, Markert T, Rajabi H, Hiraki M, Alam M, Bouillez A et al. Targeting MUC1-C suppresses Polycomb Repressive Complex 1 in multiple myeloma. Oncotarget 2017;8:69237–49.
Hernandez-Munoz I, Taghavi P, Kuijl C, Neefjes J, van Lohuizen M. Association of BMI1 with polycomb bodies is dynamic and requires PRC2/EZH2 and the maintenance DNA methyltransferase DNMT1. Mol Cell Biol. 2005;25:11047–58.
Rajabi H, Tagde A, Alam M, Bouillez A, Pitroda S, Suzuki Y, et al. DNA methylation by DNMT1 and DNMT3b methyltransferases is driven by the MUC1-C oncoprotein in human carcinoma cells. Oncogene 2016;35:6439–45.
Tagde A, Rajabi H, Stroopinsky D, Gali R, Alam M, Bouillez A, et al. MUC1-C induces DNA methyltransferase 1 and represses tumor suppressor genes in acute myeloid leukemia. Oncotarget 2016;7:38974–87.
Tam WL, Weinberg RA. The epigenetics of epithelial-mesenchymal plasticity in cancer. Nat Med. 2013;19:1438–49.
Mody HR, Hung SW, AlSaggar M, Griffin J, Govindarajan R. Inhibition of S-Adenosylmethionine-dependent methyltransferase attenuates TGFbeta1-induced EMT and metastasis in pancreatic cancer: Putative roles of miR-663a and miR-4787-5p. Mol Cancer Res. 2016;14:1124–35.
Alam M, Bouillez A, Tagde A, Ahmad R, Rajabi H, Maeda T, et al. MUC1-C represses the Crumbs complex polarity factor CRB3 and downregulates the Hippo pathway. Mol Cancer Res. 2016;14:1266–76.
Polyak K, Weinberg RA. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer. 2009;9:265–73.
Shibue T, Weinberg RA. EMT, CSCs, and drug resistance: the mechanistic link and clinical implications. Nat Rev Clin Oncol. 2017;14:611–29.
Wen Y, Cai J, Hou Y, Huang Z, Wang Z. Role of EZH2 in cancer stem cells: from biological insight to a therapeutic target. Oncotarget 2017;8:37974–90.
Park IK, Morrison SJ, Clarke MF. Bmi1, stem cells, and senescence regulation. J Clin Invest. 2004;113:175–9.
Richly H, Aloia L, Di Croce L. Roles of the Polycomb group proteins in stem cells and cancer. Cell Death Dis. 2011;2:e204.
Song LB, Li J, Liao WT, Feng Y, Yu CP, Hu LJ, et al. The polycomb group protein Bmi-1 represses the tumor suppressor PTEN and induces epithelial-mesenchymal transition in human nasopharyngeal epithelial cells. J Clin Invest. 2009;119:3626–36.
Yang MH, Hsu DS, Wang HW, Wang HJ, Lan HY, Yang WH, et al. Bmi1 is essential in Twist1-induced epithelial-mesenchymal transition. Nat Cell Biol. 2010;12:982–92.
Alam M, Rajabi H, Ahmad R, Jin C, Kufe D. Targeting the MUC1-C oncoprotein inhibits self-renewal capacity of breast cancer cells. Oncotarget 2014;5:2622–34.
Kharbanda A, Rajabi H, Jin C, Tchaicha J, Kikuchi E, Wong K, et al. Targeting the oncogenic MUC1-C protein inhibits mutant EGFR-mediated signaling and survival in non-small cell lung cancer cells. Clin Cancer Res. 2014;20:5423–34.
Alsuliman A, Colak D, Al-Harazi O, Fitwi H, Tulbah A, Al-Tweigeri T, et al. Bidirectional crosstalk between PD-L1 expression and epithelial to mesenchymal transition: significance in claudin-low breast cancer cells. Mol Cancer. 2015;14:149.
Lou Y, Diao L, Parra Cuentas ER, Denning WL, Chen L, Fan YH, et al. Epithelial-mesenchymal transition is associated with a distinct tumor microenvironment including elevation of inflammatory signals and multiple immune checkpoints in lung adenocarcinoma. Clin Cancer Res. 2016;22:3630–42.
Noman MZ, Janji B, Abdou A, Hasmim M, Terry S, Tan TZ, et al. The immune checkpoint ligand PD-L1 is upregulated in EMT-activated human breast cancer cells by a mechanism involving ZEB-1 and miR-200. Oncoimmunology 2017;6:e1263412.
Peng D, Kryczek I, Nagarsheth N, Zhao L, Wei S, Wang W, et al. Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy. Nature 2015;527:249–53.
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.
Bouillez A, Rajabi H, Jin C, Samur M, Tagde A, Alam M. et al. MUC1-C integrates PD-L1 induction with repression of immune effectors in non-small cell lung cancer. Oncogene. 2017;36:4037–46.
Bouillez A, Adeegbe D, Jin C, Hu X, Tagde A, Alam M. et al. MUC1-C promotes the suppressive immune microenvironment in non-small cell lung cancer. Oncoimmunology. 2017;6:e1338998
Agata N, Kawano T, Ahmad R, Raina D, Kharbanda S, Kufe D. MUC1 oncoprotein blocks death receptor-mediated apoptosis by inhibiting recruitment of caspase-8. Cancer Res. 2008;68:6136–44.
David JM, Hamilton DH, Palena C. MUC1 upregulation promotes immune resistance in tumor cells undergoing brachyury-mediated epithelial-mesenchymal transition. Oncoimmunology 2016;5:e1117738.
Mak MP, Tong P, Diao L, Cardnell RJ, Gibbons DL, William WN, et al. A patient-derived, pan-cancer EMT signature identifies global molecular alterations and immune target enrichment following epithelial-to-mesenchymal transition. Clin Cancer Res. 2016;22:609–20.
Dongre A, Rashidian M, Reinhardt F, Bagnato A, Keckesova Z, Ploegh HL, et al. Epithelial-to-mesenchymal transition contributes to immunosuppression in breast carcinomas. Cancer Res. 2017;77:3982–9.
Singh A, Settleman J. EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene 2010;29:4741–51.
Ren J, Agata N, Chen D, Li Y, Yu W-H, Huang L, et al. Human MUC1 carcinoma-associated protein confers resistance to genotoxic anti-cancer agents. Cancer Cell. 2004;5:163–75.
Kharbanda A, Rajabi H, Jin C, Raina D, Kufe D. MUC1-C oncoprotein induces tamoxifen resistance in human breast cancer. Mol Cancer Res. 2013;11:714–23.
Nath S, Daneshvar K, Roy LD, Grover P, Kidiyoor A, Mosley L, et al. MUC1 induces drug resistance in pancreatic cancer cells via upregulation of multidrug resistance genes. Oncogenesis. 2013;2:e51.
Prakash R, Zhang Y, Feng W, Jasin M. Homologous recombination and human health: the roles of BRCA1, BRCA2, and associated proteins. Cold Spring Harb Perspect Biol. 2015;7:a016600.
Lin X, Ojo D, Wei F, Wong N, Gu Y, Tang D. A novel aspect of tumorigenesis-BMI1 functions in regulating DNA damage response. Biomolecules. 2015;5:3396–415.
Raina D, Agarwal P, Lee J, Bharti A, McKnight C, Sharma P, et al. Characterization of the MUC1-C cytoplasmic domain as a cancer target. PLoS ONE. 2015;10:e0135156.
Dyson HJ, Wright PE. Intrinsically unstructured proteins and their functions. Nat Rev Mol Cell Biol. 2005;6:197–208.
Kufe D. Functional targeting of the MUC1 oncogene in human cancers. Canc Bio Ther. 2009;8:1201–7.
Uchida Y, Raina D, Kharbanda S, Kufe D. Inhibition of the MUC1-C oncoprotein is synergistic with cytotoxic agents in treatment of breast cancer cells. Canc Bio Ther. 2013;14:127–34.
Hasegawa M, Sinha RK, Kumar M, Alam M, Yin L, Raina D, et al. Intracellular targeting of the oncogenic MUC1-C protein with a novel GO-203 nanoparticle formulation. Clin Cancer Res. 2015;21:2338–47.
Stroopinsky D, Rosenblatt J, Ito K, Mills H, Yin L, Rajabi H, et al. MUC1 is a potential target for the treatment of acute myeloid leukemia stem cells. Cancer Res. 2013;73:5569–79.
Butts C, Socinski MA, Mitchell PL, Thatcher N, Havel L, Krzakowski M, et al. Tecemotide (L-BLP25) versus placebo after chemoradiotherapy for stage III non-small-cell lung cancer (START): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2014;15:59–68.
Quoix E, Lena H, Losonczy G, Forget F, Chouaid C, Papai Z, et al. TG4010 immunotherapy and first-line chemotherapy for advanced non-small-cell lung cancer (TIME): results from the phase 2b part of a randomised, double-blind, placebo-controlled, phase 2b/3 trial. Lancet Oncol. 2015;17:212–23.
Gong J, Chen D, Kashiwaba M, Li Y, Takeuchi H, Qu H, et al. Reversal of tolerance to human MUC1 antigen in MUC1 transgenic mice immunized with fusions of dendritic and carcinoma cells. Proc Natl Acad Sci USA. 1998;95:6279–83.
Rosenblatt J, Avivi I, Vasir B, Uhl L, Munshi NC, Katz T, et al. Vaccination with dendritic cell/tumor fusions following autologous stem cell transplant induces immunologic and clinical responses in multiple myeloma patients. Clin Cancer Res. 2013;19:3640–8.
Rosenblatt J, Stone R, Uhl L, Neuberg D, Joyce R, Levine J et al. Individualized vaccination of AML patients in remission is associated with induction of antileukemia immunity and prolonged remissions. Sci Transl Med. 2016;8:368ra171.
Li LC, Dahiya R. MethPrimer: designing primers for methylation PCRs. Bioinformatics 2002;18:1427–31.
Muller H, Bracken AP, Vernell R, Moroni MC, Christians F, Grassilli E, et al. E2Fs regulate the expression of genes involved in differentiation, development, proliferation, and apoptosis. Genes Dev. 2001;15:267–85.
Dyson HJ, Wright PE. Role of intrinsic protein disorder in the Function and interactions of the transcriptional coactivators CREB-binding protein (CBP) and p300. J Biol Chem. 2016;291:6714–22.
Maeda T, Hiraki M, Jin C, Rajabi H, Tagde A, Alam M et al. MUC1-C induces PD-L1 and immune evasion in triple-negative breast cancer. Cancer Res. 2018; 78: 205–15.
This publication was supported by the US Department of Defense under award number BC151648 and the National Cancer Institute of the National Institutes of Health under award numbers R01CA097098, R01CA166480 and R21CA216553.
Conflict of interest
DK has ownership interest (including patents) and is a consultant/advisory board member of Genus Oncology. No potential conflicts of interest were disclosed by the other authors.
About this article
Cite this article
Rajabi, H., Hiraki, M. & Kufe, D. MUC1-C activates polycomb repressive complexes and downregulates tumor suppressor genes in human cancer cells. Oncogene 37, 2079–2088 (2018). https://doi.org/10.1038/s41388-017-0096-9
International Immunopharmacology (2020)
Nature Communications (2020)
JCI Insight (2020)
JCI Insight (2018)