Cooperation Between MYC and β-Catenin in Liver Tumorigenesis Requires Yap/Taz.
Adaptor Proteins, Signal Transducing
/ physiology
Animals
Cell Cycle Proteins
/ physiology
Liver Neoplasms, Experimental
/ etiology
Mice
Mice, Inbred C57BL
Proto-Oncogene Proteins c-myc
/ physiology
Trans-Activators
/ physiology
Wnt Signaling Pathway
/ physiology
YAP-Signaling Proteins
beta Catenin
/ physiology
Journal
Hepatology (Baltimore, Md.)
ISSN: 1527-3350
Titre abrégé: Hepatology
Pays: United States
ID NLM: 8302946
Informations de publication
Date de publication:
10 2020
10 2020
Historique:
received:
18
10
2019
accepted:
20
12
2019
pubmed:
23
1
2020
medline:
4
5
2021
entrez:
23
1
2020
Statut:
ppublish
Résumé
Activation of MYC and catenin beta-1 (CTNNB1, encoding β-catenin) can co-occur in liver cancer, but how these oncogenes cooperate in tumorigenesis remains unclear. We generated a mouse model allowing conditional activation of MYC and WNT/β-catenin signaling (through either β-catenin activation or loss of APC - adenomatous polyposis coli) upon expression of CRE recombinase in the liver and monitored their effects on hepatocyte proliferation, apoptosis, gene expression profiles, and tumorigenesis. Activation of WNT/β-catenin signaling strongly accelerated MYC-driven carcinogenesis in the liver. Both pathways also cooperated in promoting cellular transformation in vitro, demonstrating their cell-autonomous action. Short-term induction of MYC and β-catenin in hepatocytes, followed by RNA-sequencing profiling, allowed the identification of a "Myc/β-catenin signature," composed of a discrete set of Myc-activated genes whose expression increased in the presence of active β-catenin. Notably, this signature enriched for targets of Yes-associated protein (Yap) and transcriptional coactivator with PDZ-binding motif (Taz), two transcriptional coactivators known to be activated by WNT/β-catenin signaling and to cooperate with MYC in mitogenic activation and liver transformation. Consistent with these regulatory connections, Yap/Taz accumulated upon Myc/β-catenin activation and were required not only for the ensuing proliferative response, but also for tumor cell growth and survival. Finally, the Myc/β-catenin signature was enriched in a subset of human hepatocellular carcinomas characterized by comparatively poor prognosis. Myc and β-catenin show a strong cooperative action in liver carcinogenesis, with Yap and Taz serving as mediators of this effect. These findings warrant efforts toward therapeutic targeting of Yap/Taz in aggressive liver tumors marked by elevated Myc/β-catenin activity.
Sections du résumé
BACKGROUND AND AIMS
Activation of MYC and catenin beta-1 (CTNNB1, encoding β-catenin) can co-occur in liver cancer, but how these oncogenes cooperate in tumorigenesis remains unclear.
APPROACH AND RESULTS
We generated a mouse model allowing conditional activation of MYC and WNT/β-catenin signaling (through either β-catenin activation or loss of APC - adenomatous polyposis coli) upon expression of CRE recombinase in the liver and monitored their effects on hepatocyte proliferation, apoptosis, gene expression profiles, and tumorigenesis. Activation of WNT/β-catenin signaling strongly accelerated MYC-driven carcinogenesis in the liver. Both pathways also cooperated in promoting cellular transformation in vitro, demonstrating their cell-autonomous action. Short-term induction of MYC and β-catenin in hepatocytes, followed by RNA-sequencing profiling, allowed the identification of a "Myc/β-catenin signature," composed of a discrete set of Myc-activated genes whose expression increased in the presence of active β-catenin. Notably, this signature enriched for targets of Yes-associated protein (Yap) and transcriptional coactivator with PDZ-binding motif (Taz), two transcriptional coactivators known to be activated by WNT/β-catenin signaling and to cooperate with MYC in mitogenic activation and liver transformation. Consistent with these regulatory connections, Yap/Taz accumulated upon Myc/β-catenin activation and were required not only for the ensuing proliferative response, but also for tumor cell growth and survival. Finally, the Myc/β-catenin signature was enriched in a subset of human hepatocellular carcinomas characterized by comparatively poor prognosis.
CONCLUSIONS
Myc and β-catenin show a strong cooperative action in liver carcinogenesis, with Yap and Taz serving as mediators of this effect. These findings warrant efforts toward therapeutic targeting of Yap/Taz in aggressive liver tumors marked by elevated Myc/β-catenin activity.
Substances chimiques
Adaptor Proteins, Signal Transducing
0
CTNNB1 protein, mouse
0
Cell Cycle Proteins
0
Myc protein, mouse
0
Proto-Oncogene Proteins c-myc
0
Trans-Activators
0
Wwtr1 protein, mouse
0
YAP-Signaling Proteins
0
Yap1 protein, mouse
0
beta Catenin
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1430-1443Subventions
Organisme : European Research Council
ID : 268671-MYCNEXT
Pays : International
Organisme : Worldwide Cancer Research
ID : 15-1260
Pays : United Kingdom
Informations de copyright
© 2020 by the American Association for the Study of Liver Diseases.
Références
Zucman-Rossi J, Villanueva A, Nault JC, Llovet JM. Genetic landscape and biomarkers of hepatocellular carcinoma. Gastroenterology 2015;149:1226-1239.e4.
Schulze K, Imbeaud S, Letouze E, Alexandrov LB, Calderaro J, Rebouissou S, et al. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat Genet 2015;47:505-511.
Cancer Genome Atlas Research Network. Comprehensive and integrative genomic characterization of hepatocellular carcinoma. Cell 2017;169:1327-1341.e23.
Nusse R, Clevers H. Wnt/β-catenin signaling, disease, and emerging therapeutic modalities. Cell 2017;169:985-999.
de La Coste A, Romagnolo B, Billuart P, Renard CA, Buendia MA, Soubrane O, et al. Somatic mutations of the β-catenin gene are frequent in mouse and human hepatocellular carcinomas. Proc Natl Acad Sci U S A 1998;95:8847-8851.
Sansom OJ, Meniel VS, Muncan V, Phesse TJ, Wilkins JA, Reed KR, et al. Myc deletion rescues APC deficiency in the small intestine. Nature 2007;446:676-679.
Wong CS, Chen C, Wu Q, Liu Y, Zheng P. A critical role for the regulated Wnt-Myc pathway in naive T cell survival. J Immunol 2015;194:158-167.
Shu WG, Guttentag S, Wang ZS, Andl T, Ballard P, Lu MM, et al. Wnt/beta-catenin signaling acts upstream of N-myc, BMP4, and FGF signaling to regulate proximal-distal patterning in the lung. Dev Biol 2005;283:226-239.
Colnot S, Decaens T, Niwa-Kawakita M, Godard C, Hamard G, Kahn A, et al. Liver-targeted disruption of APC in mice activates beta-catenin signaling and leads to hepatocellular carcinomas. Proc Natl Acad Sci U S A 2004;101:17216-17221.
Reed KR, Athineos D, Meniel VS, Wilkins JA, Ridgway RA, Burke ZD, et al. B-catenin deficiency, but not Myc deletion, suppresses the immediate phenotypes of APC loss in the liver. Proc Natl Acad Sci U S A 2008;105:18919-18923.
Burke ZD, Reed KR, Phesse TJ, Sansom OJ, Clarke AR, Tosh D. Liver zonation occurs through a β-catenin-dependent, c-Myc-independent mechanism. Gastroenterology 2009;136:2316-2324.e1-3.
Kaveri D, Kastner P, Dembele D, Nerlov C, Chan S, Kirstetter P. β-Catenin activation synergizes with Pten loss and Myc overexpression in Notch-independent T-ALL. Blood 2013;122:694-704.
Cairo S, Armengol C, De Reynies A, Wei Y, Thomas E, Renard CA, et al. Hepatic stem-like phenotype and interplay of Wnt/β-catenin and Myc signaling in aggressive childhood liver cancer. Cancer Cell 2008;14:471-484.
Yim SY, Shim JJ, Shin JH, Jeong YS, Kang SH, Kim SB, et al. Integrated genomic comparison of mouse models reveals their clinical resemblance to human liver cancer. Mol Cancer Res 2018;16:1713-1723.
Calvisi DF, Factor VM, Loi R, Thorgeirsson SS. Activation of beta-catenin during hepatocarcinogenesis in transgenic mouse models: relationship to phenotype and tumor grade. Cancer Res 2001;61:2085-2091.
Schuler M, Dierich A, Chambon P, Metzger D. Efficient temporally controlled targeted somatic mutagenesis in hepatocytes of the mouse. Genesis 2004;39:167-172.
Harada N, Tamai Y, Ishikawa T, Sauer B, Takaku K, Oshima M, et al. Intestinal polyposis in mice with a dominant stable mutation of the beta-catenin gene. EMBO J 1999;18:5931-5942.
Azzolin L, Panciera T, Soligo S, Enzo E, Bicciato S, Dupont S, et al. YAP/TAZ incorporation in the beta-catenin destruction complex orchestrates the Wnt response. Cell 2014;158:157-170.
Colnot S, Niwa-Kawakita M, Hamard G, Godard C, Le Plenier S, Houbron C, et al. Colorectal cancers in a new mouse model of familial adenomatous polyposis: influence of genetic and environmental modifiers. Lab Invest 2004;84:1619-1630.
Calado DP, Sasaki Y, Godinho SA, Pellerin A, Kochert K, Sleckman BP, et al. The cell-cycle regulator c-Myc is essential for the formation and maintenance of germinal centers. Nat Immunol 2012;13:1092-1100.
de Galarreta MR, Bresnahan E, Molina-Sanchez P, Lindblad KE, Maier B, Sia D, et al. β-catenin activation promotes immune escape and resistance to anti-PD-1 therapy in hepatocellular carcinoma. Cancer Discov 2019;9:1124-1141.
Harada N, Miyoshi H, Murai N, Oshima H, Tamai Y, Oshima M, et al. Lack of tumorigenesis in the mouse liver after adenovirus-mediated expression of a dominant stable mutant of beta-catenin. Cancer Res 2002;62:1971-1977.
Kristianto J, Johnson MG, Zastrow RK, Radcliff AB, Blank RD. Spontaneous recombinase activity of Cre-ERT2 in vivo. Transgenic Res 2017;26:411-417.
Yimlamai D, Christodoulou C, Galli GG, Yanger K, Pepe-Mooney B, Gurung B, et al. Hippo pathway activity influences liver cell fate. Cell 2014;157:1324-1338.
Sabo A, Kress TR, Pelizzola M, de Pretis S, Gorski MM, Tesi A, et al. Selective transcriptional regulation by Myc in cellular growth control and lymphomagenesis. Nature 2014;511:488-492.
Valenta T, Gay M, Steiner S, Draganova K, Zemke M, Hoffmans R, et al. Probing transcription-specific outputs of beta-catenin in vivo. Genes Dev 2011;25:2631-2643.
Kress TR, Pellanda P, Pellegrinet L, Bianchi V, Nicoli P, Doni M, et al. Identification of MYC-dependent transcriptional programs in oncogene-addicted liver tumors. Cancer Res 2016;76:3463-3472.
Zanconato F, Forcato M, Battilana G, Azzolin L, Quaranta E, Bodega B, et al. Genome-wide association between YAP/TAZ/TEAD and AP-1 at enhancers drives oncogenic growth. Nat Cell Biol 2015;17:1218-1227.
Pattschull G, Walz S, Grundl M, Schwab M, Ruhl E, Baluapuri A, et al. The Myb-MuvB complex is required for YAP-dependent transcription of mitotic genes. Cell Rep 2019;27:3533-3546.e7.
Azzolin L, Zanconato F, Bresoli S, Forcato M, Basso G, Bicciato S, et al. Role of TAZ as mediator of Wnt signaling. Cell 2012;151:1443-1456.
Croci O, De Fazio S, Biagioni F, Donato E, Caganova M, Curti L, et al. Transcriptional integration of mitogenic and mechanical signals by Myc and YAP. Genes Dev 2017;31:2017-2022.
Liberzon A, Birger C, Thorvaldsdottir H, Ghandi M, Mesirov JP, Tamayo P. The Molecular Signatures Database (MSigDB) hallmark gene set collection. Cell Syst 2015;1:417-425.
Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A 2005;102:15545-15550.
Donato E, Biagioni F, Bisso A, Caganova M, Amati B, Campaner S. YAP and TAZ are dispensable for physiological and malignant haematopoiesis. Leukemia 2018;32:2037-2040.
You Z, Saims D, Chen S, Zhang Z, Guttridge DC, Guan KL, et al. Wnt signaling promotes oncogenic transformation by inhibiting c-Myc-induced apoptosis. J Cell Biol 2002;157:429-440.
Cai J, Maitra A, Anders RA, Taketo MM, Pan D. β-catenin destruction complex-independent regulation of Hippo-YAP signaling by APC in intestinal tumorigenesis. Genes Dev 2015;29:1493-1506.
Zanconato F, Cordenonsi M, Piccolo S. YAP/TAZ at the roots of cancer. Cancer Cell 2016;29:783-803.
Park HW, Kim YC, Yu B, Moroishi T, Mo JS, Plouffe SW, et al. Alternative Wnt signaling activates YAP/TAZ. Cell 2015;162:780-794.
Zanconato F, Battilana G, Forcato M, Filippi L, Azzolin L, Manfrin A, et al. Transcriptional addiction in cancer cells is mediated by YAP/TAZ through BRD4. Nat Med 2018;24:1599-1610.
Kalkat M, Resetca D, Lourenco C, Chan PK, Wei Y, Shiah YJ, et al. MYC protein interactome profiling reveals functionally distinct regions that cooperate to drive tumorigenesis. Mol Cell 2018;72:836-848.e837.
Muhar M, Ebert A, Neumann T, Umkehrer C, Jude J, Wieshofer C, et al. SLAM-seq defines direct gene-regulatory functions of the BRD4-MYC axis. Science 2018;360:800-805.
Sabò A, Amati B. BRD4 and MYC-clarifying regulatory specificity. Science 2018;360:713-714.
Donato E, Croci O, Sabo A, Muller H, Morelli MJ, Pelizzola M, et al. Compensatory RNA polymerase 2 loading determines the efficacy and transcriptional selectivity of JQ1 in Myc-driven tumors. Leukemia 2017;31:479-490.
Hoshida Y, Nijman SM, Kobayashi M, Chan JA, Brunet JP, Chiang DY, et al. Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma. Cancer Res 2009;69:7385-7392.
Rosenbluh J, Nijhawan D, Cox AG, Li X, Neal JT, Schafer EJ, et al. β-Catenin-driven cancers require a YAP1 transcriptional complex for survival and tumorigenesis. Cell 2012;151:1457-1473.
Sanchez-Vega F, Mina M, Armenia J, Chatila WK, Luna A, La KC, et al. Oncogenic signaling pathways in the cancer genome atlas. Cell 2018;173:321-337.e310.
Sohn BH, Shim JJ, Kim SB, Jang KY, Kim SM, Kim JH, et al. Inactivation of hippo pathway is significantly associated with poor prognosis in hepatocellular carcinoma. Clin Cancer Res 2016;22:1256-1264.
Tao J, Calvisi DF, Ranganathan S, Cigliano A, Zhou L, Singh S, et al. Activation of beta-catenin and Yap1 in human hepatoblastoma and induction of hepatocarcinogenesis in mice. Gastroenterology 2014;147:690-701.
Zanconato F, Battilana G, Cordenonsi M, Piccolo S. YAP/TAZ as therapeutic targets in cancer. Curr Opin Pharmacol 2016;29:26-33.
Lu L, Finegold MJ, Johnson RL. Hippo pathway coactivators Yap and Taz are required to coordinate mammalian liver regeneration. Exp Mol Med 2018;50:e423.
Sorrentino G, Ruggeri N, Specchia V, Cordenonsi M, Mano M, Dupont S, et al. Metabolic control of YAP and TAZ by the mevalonate pathway. Nat Cell Biol 2014;16:357-366.
Wang Z, Wu Y, Wang H, Zhang Y, Mei L, Fang X, et al. Interplay of mevalonate and Hippo pathways regulates RHAMM transcription via YAP to modulate breast cancer cell motility. Proc Natl Acad Sci U S A 2014;111:E89-E98.
Higashi T, Hayashi H, Kitano Y, Yamamura K, Kaida T, Arima K, et al. Statin attenuates cell proliferative ability via TAZ (WWTR1) in hepatocellular carcinoma. Med Oncol 2016;33:123.
Singh S, Singh PP, Singh AG, Murad MH, Sanchez W. Statins are associated with a reduced risk of hepatocellular cancer: a systematic review and meta-analysis. Gastroenterology 2013;144:323-332.
Nielsen SF, Nordestgaard BG, Bojesen SE. Statin use and reduced cancer-related mortality. N Engl J Med 2012;367:1792-802.