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Nuclear partitioning of Prohibitin 1 inhibits Wnt/β-catenin-dependent intestinal tumorigenesis

Oncogene volume 40, pages 369–383 (2021)Cite this article

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Abstract

The Wnt/β-catenin signaling pathway is aberrantly activated in the majority of colorectal cancer cases due to somatic mutations in the adenomatous polyposis coli (APC) gene. Prohibitin 1 (PHB1) serves pleiotropic cellular functions with dynamic subcellular trafficking, facilitating signaling crosstalk between organelles. Nuclear-localized PHB1 is an important regulator of gene transcription. Using mice with inducible intestinal epithelial cell (IEC)-specific deletion of Phb1 (Phb1iΔIEC) and mice with IEC-specific overexpression of Phb1 (Phb1Tg), we demonstrate that IEC-specific PHB1 combats intestinal tumorigenesis in the ApcMin/+ mouse model by inhibiting Wnt/β-catenin signaling. Forced nuclear accumulation of PHB1 in human RKO or SW48 CRC cell lines increased AXIN1 expression and decreased cell viability. PHB1 deficiency in CRC cells decreased AXIN1 expression and increased β-catenin activation that was abolished by XAV939, a pharmacological AXIN stabilizer. These results define a role of PHB1 in inhibiting the Wnt/β-catenin pathway to influence the development of intestinal tumorigenesis. Induction of nuclear PHB1 trafficking provides a novel therapeutic option to influence AXIN1 expression and the β-catenin destruction complex in Wnt-driven intestinal tumorigenesis.

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Fig. 1: PHB1 expression inversely correlates with β-catenin expression in adenomas.
Fig. 2: Phb1 deletion in IECs increases intestinal tumorigenesis in ApcMin/+ mice.
Fig. 3: Phb1i∆IEC/ApcMin/+ mice exhibit increased proliferation in adenomas and colonic IECs.
Fig. 4: β-catenin activation is increased in Phb1i∆IEC mice.
Fig. 5: IEC-specific Phb1 overexpression ameliorates intestinal tumorigenesis in ApcMin/+ mice.
Fig. 6: Phb1Tg/ApcMin/+ mice exhibit decreased proliferation in adenomas compared to ApcMin/+ mice.
Fig. 7: β-catenin activation in adenomas is inhibited in Phb1Tg/ApcMin/+ mice.
Fig. 8: Relative expression of PHB1 regulates β-catenin activation and cell viability in RKO and SW48 CRC cell lines.

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References

  1. Arnold M, Sierra MS, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global patterns and trends in colorectal cancer incidence and mortality. Gut. 2017;66:683–91.

    Article  Google Scholar 

  2. 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.

    Article  Google Scholar 

  3. Barker N, Ridgway RA, van Es JH, van de Wetering M, Begthel H, van den Born M, et al. Crypt stem cells as the cells-of-origin of intestinal cancer. Nature. 2009;457:608–11.

    Article  CAS  Google Scholar 

  4. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990;61:759–67.

    Article  CAS  Google Scholar 

  5. Schatoff EM, Leach BI, Dow LE. Wnt signaling and colorectal cancer. Curr Colorectal Cancer Rep. 2017;13:101–10.

    Article  Google Scholar 

  6. Behrens J, Jerchow BA, Wurtele M, Grimm J, Asbrand C, Wirtz R, et al. Functional interaction of an axin homolog, conductin, with beta-catenin, APC, and GSK3beta. Science. 1998;280:596–9.

    Article  CAS  Google Scholar 

  7. Delgado-Deida Y, Alula KM, Theiss AL. The influence of mitochondrial-directed regulation of Wnt signaling on tumorigenesis. Gastroenterol Rep. 2020;8:215–23.

    Article  Google Scholar 

  8. Basmadjian C, Thuaud F, Ribeiro N, Desaubry L. Flavaglines: potent anticancer drugs that target prohibitins and the helicase eIF4A. Future Med Chem. 2013;5:2185–97.

    Article  CAS  Google Scholar 

  9. Thuaud F, Ribeiro N, Nebigil CG, Desaubry L. Prohibitin ligands in cell death and survival: mode of action and therapeutic potential. Chem Biol. 2013;20:316–31.

    Article  CAS  Google Scholar 

  10. Rastogi S, Joshi B, Fusaro G, Chellappan S. Camptothecin induces nuclear export of prohibitin preferentially in transformed cells through a CRM-1-dependent mechanism. J Biol Chem. 2006;281:2951–9.

    Article  CAS  Google Scholar 

  11. Zhou TB, Qin YH. Signaling pathways of prohibitin and its role in diseases. J Recept Signal Transduct Res. 2013;33:28–36.

    Article  Google Scholar 

  12. Wang D, Tabti R, Elderwish S, Abou-Hamdan H, Djehal A, Yu P, et al. Prohibitin ligands: a growing armamentarium to tackle cancers, osteoporosis, inflammatory, cardiac and neurological diseases. Cell Mol Life Sci. 2020;77:3525–46.

  13. Ma LL, Shen L, Tong GH, Tang N, Luo Y, Guo LL, et al. Prohibitin, relocated to the front ends, can control the migration directionality of colorectal cancer cells. Oncotarget. 2017;8:76340–56.

    Article  Google Scholar 

  14. Theiss AL, Idell RD, Srinivasan S, Klapproth JM, Jones DP, Merlin D, et al. Prohibitin protects against oxidative stress in intestinal epithelial cells. FASEB J. 2007;21:197–206.

    Article  CAS  Google Scholar 

  15. Chiu CF, Ho MY, Peng JM, Hung SW, Lee WH, Liang CM, et al. Raf activation by Ras and promotion of cellular metastasis require phosphorylation of prohibitin in the raft domain of the plasma membrane. Oncogene. 2013;32:777–87.

    Article  CAS  Google Scholar 

  16. Jackson DN, Panopoulos M, Neumann WL, Turner K, Cantarel BL, Thompson-Snipes L, et al. Mitochondrial dysfunction during loss of prohibitin 1 triggers Paneth cell defects and ileitis. Gut. 2020;69:1928–38.

  17. Cormier RT, Bilger A, Lillich AJ, Halberg RB, Hong KH, Gould KA, et al. The Mom1AKR intestinal tumor resistance region consists of Pla2g2a and a locus distal to D4Mit64. Oncogene. 2000;19:3182–92.

    Article  CAS  Google Scholar 

  18. Jackson DN, Alula KM, Delgado-Deida Y, Tabti R, Turner K, Wang X, et al. The synthetic small molecule FL3 combats intestinal tumorigenesis via Axin1-mediated inhibition of Wnt/beta-catenin signaling. Cancer Res. 2020;80:3519–29.

  19. Theiss AL, Vijay-Kumar M, Obertone TS, Jones DP, Hansen JM, Gewirtz AT, et al. Prohibitin is a novel regulator of antioxidant response that attenuates colonic inflammation in mice. Gastroenterology. 2009;137:199–208. 208 e191-196.

    Article  CAS  Google Scholar 

  20. Theiss AL, Sitaraman SV. The role and therapeutic potential of prohibitin in disease. Biochim Biophys Acta. 2011;1813:1137–43.

    Article  CAS  Google Scholar 

  21. Chen D, Chen F, Lu X, Yang X, Xu Z, Pan J, et al. Identification of prohibitin as a potential biomarker for colorectal carcinoma based on proteomics technology. Int J Oncol. 2010;37:355–65.

    CAS  PubMed  Google Scholar 

  22. Hammoudi A, Song F, Reed KR, Jenkins RE, Meniel VS, Watson AJ, et al. Proteomic profiling of a mouse model of acute intestinal Apc deletion leads to identification of potential novel biomarkers of human colorectal cancer (CRC). Biochem Biophys Res Commun. 2013;440:364–70.

    Article  CAS  Google Scholar 

  23. Kathiria AS, Neumann WL, Rhees J, Hotchkiss E, Cheng Y, Genta RM, et al. Prohibitin attenuates colitis-associated tumorigenesis in mice by modulating p53 and STAT3 apoptotic responses. Cancer Res. 2012;72:5778–89.

    Article  CAS  Google Scholar 

  24. Peng YT, Chen P, Ouyang RY, Song L. Multifaceted role of prohibitin in cell survival and apoptosis. Apoptosis. 2015;20:1135–49.

    Article  CAS  Google Scholar 

  25. Tortelote GG, Reis RR, de Almeida Mendes F, Abreu JG. Complexity of the Wnt/betacatenin pathway: searching for an activation model. Cell Signal. 2017;40:30–43.

    Article  CAS  Google Scholar 

  26. Krishnamurthy N, Kurzrock R. Targeting the Wnt/beta-catenin pathway in cancer: update on effectors and inhibitors. Cancer Treat Rev. 2018;62:50–60.

    Article  CAS  Google Scholar 

  27. Mavila N, Tang Y, Berlind J, Ramani K, Wang J, Mato JM, et al. Prohibitin 1 acts as a negative regulator of wingless/integrated-beta-catenin signaling in murine liver and human liver. Cancer Cells Hepatol Commun. 2018;2:1583–600.

    Article  CAS  Google Scholar 

  28. Chowdhury D, Kumar D, Sarma P, Tangutur AD, Bhadra MP. PHB in cardiovascular and other diseases: present knowledge and implications. Curr Drug Targets. 2017;18:1836–51.

    Article  CAS  Google Scholar 

  29. Bourges I, Ramus C, Mousson de Camaret B, Beugnot R, Remacle C, Cardol P, et al. Structural organization of mitochondrial human complex I: role of the ND4 and ND5 mitochondria-encoded subunits and interaction with prohibitin. Biochem J. 2004;383:491–9.

    Article  CAS  Google Scholar 

  30. Hsieh SY, Shih TC, Yeh CY, Lin CJ, Chou YY, Lee YS. Comparative proteomic studies on the pathogenesis of human ulcerative colitis. Proteomics. 2006;6:5322–31.

    Article  CAS  Google Scholar 

  31. Tsutsumi T, Matsuda M, Aizaki H, Moriya K, Miyoshi H, Fujie H, et al. Proteomics analysis of mitochondrial proteins reveals overexpression of a mitochondrial protein chaperon, prohibitin, in cells expressing hepatitis C virus core protein. Hepatology. 2009;50:378–86.

    Article  CAS  Google Scholar 

  32. Yu L, Lu M, Jia D, Ma J, Ben-Jacob E, Levine H, et al. Modeling the genetic regulation of cancer metabolism: interplay between glycolysis and oxidative phosphorylation. Cancer Res. 2017;77:1564–74.

    Article  CAS  Google Scholar 

  33. Kim DM, Jang H, Shin MG, Kim JH, Shin SM, Min SH, et al. beta-catenin induces expression of prohibitin gene in acute leukemic cells. Oncol Rep. 2017;37:3201–8.

    Article  CAS  Google Scholar 

  34. Chia IV, Costantini F. Mouse axin and axin2/conductin proteins are functionally equivalent in vivo. Mol Cell Biol. 2005;25:4371–6.

    Article  CAS  Google Scholar 

  35. Leung JY, Kolligs FT, Wu R, Zhai Y, Kuick R, Hanash S, et al. Activation of AXIN2 expression by beta-catenin-T cell factor. A feedback repressor pathway regulating Wnt signaling. J Biol Chem. 2002;277:21657–65.

    Article  CAS  Google Scholar 

  36. Wang Z, Tacchelly-Benites O, Yang E, Thorne CA, Nojima H, Lee E, et al. Wnt/wingless pathway activation is promoted by a critical threshold of axin maintained by the tumor suppressor APC and the ADP-ribose polymerase tankyrase. Genetics. 2016;203:269–81.

    Article  CAS  Google Scholar 

  37. Lau T, Chan E, Callow M, Waaler J, Boggs J, Blake RA, et al. A novel tankyrase small-molecule inhibitor suppresses APC mutation-driven colorectal tumor growth. Cancer Res. 2013;73:3132–44.

    Article  CAS  Google Scholar 

  38. Ko KS, Tomasi ML, Iglesias-Ara A, French BA, French SW, Ramani K, et al. Liver-specific deletion of prohibitin 1 results in spontaneous liver injury, fibrosis, and hepatocellular carcinoma in mice. Hepatology. 2010;52:2096–108.

    Article  CAS  Google Scholar 

  39. Jackson DN, Theiss AL. Gut bacteria signaling to mitochondria in intestinal inflammation and cancer. Gut Microbes. 2020;11:285–304.

    Article  Google Scholar 

  40. el Marjou F, Janssen KP, Chang BH, Li M, Hindie V, Chan L, et al. Tissue-specific and inducible Cre-mediated recombination in the gut epithelium. Genesis. 2004;39:186–93.

    Article  CAS  Google Scholar 

  41. Nenci A, Becker C, Wullaert A, Gareus R, van Loo G, Danese S, et al. Epithelial NEMO links innate immunity to chronic intestinal inflammation. Nature. 2007;446:557–61.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Jie Han (Baylor Scott & White Research Institute) for technical assistance. This work was supported by National Institutes of Health grants R01-DK117001 (ALT), Litwin IBD Pioneers Crohn’s Colitis Foundation 301869 (ALT), and GI & Liver Innate Immune Program (GALIIP)—University of Colorado Anschutz (ALT).

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Authors and Affiliations

  1. Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado, Aurora, CO, USA

    Kibrom M. Alula, Yaritza Delgado-Deida & Arianne L. Theiss

  2. Department of Internal Medicine, Division of Gastroenterology, Baylor Scott & White Research Institute, Baylor University Medical Center, Dallas, TX, USA

    Dakota N. Jackson

  3. University of Texas Southwestern Medical Center, College of Medicine, Dallas, TX, USA

    K. Venuprasad

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Contributions

Study concept and design: KV, ALT. Acquisition of data: DNJ, KMA, YDD, ALT. Analysis and interpretation of data: KV, ALT. Drafting the manuscript: KMA, ALT. Critical revision of the manuscript for important intellectual content: KV.

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Correspondence to Arianne L. Theiss.

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Alula, K.M., Delgado-Deida, Y., Jackson, D.N. et al. Nuclear partitioning of Prohibitin 1 inhibits Wnt/β-catenin-dependent intestinal tumorigenesis. Oncogene 40, 369–383 (2021). https://doi.org/10.1038/s41388-020-01538-y

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