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Cell type-dependent function of LATS1/2 in cancer cell growth

Abstract

The Hippo pathway controls organ size and tissue homeostasis, and its dysregulation often contributes to tumorigenesis. Extensive studies have shown that the Hippo pathway inhibits cell proliferation, and survival in a cell-autonomous manner. We examined the function of the Hippo pathway kinases LATS1/2 (large tumor suppressor 1 and 2) in cancer cells. As expected, loss of LATS1/2 promotes cancer cell growth in most cell lines. Surprisingly, however, LATS1/2 deletion inhibits the growth of murine MC38 colon cancer cells, especially under detachment conditions. This growth inhibitory effect caused by LATS1/2 deletion is due to uncontrolled activation of Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), the key downstream transcriptional coactivators inhibited by LATS1/2. We identified Wnt inducible signaling pathway protein 2 (Wisp2) and coiled-coil domain containing 80 (Ccdc80) as direct targets of YAP/TAZ. Their expression is selectively induced by LATS1/2 deletion in MC38 cells. Furthermore, deletion of WISP2 and CCDC80 prevents the growth inhibitory effect of LATS1/2 loss in MC38 cells. Our study demonstrates that the function of LATS1/2 in cell growth is cell context dependent, suggesting that LATS1/2 inhibition can be a therapeutic approach for some cancer types.

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References

  1. 1.

    Pan D. The hippo signaling pathway in development and cancer. Dev Cell. 2010;19:491–505.

  2. 2.

    Johnson R, Halder G. The two faces of Hippo: targeting the Hippo pathway for regenerative medicine and cancer treatment. Nat Rev Drug Discov. 2014;13:63–79.

  3. 3.

    Yu FX, Zhao B, Guan KL. Hippo pathway in organ size control, tissue homeostasis, and cancer. Cell. 2015;163:811–28.

  4. 4.

    Barry ER, Camargo FD. The Hippo superhighway: signaling crossroads converging on the Hippo/Yap pathway in stem cells and development. Curr Opin Cell Biol. 2013;25:247–53.

  5. 5.

    Harvey KF, Zhang X, Thomas DM. The Hippo pathway and human cancer. Nat Rev Cancer. 2013;13:246–57.

  6. 6.

    Moroishi T, Hansen CG, Guan KL. The emerging roles of YAP and TAZ in cancer. Nat Rev Cancer. 2015;15:73–9.

  7. 7.

    Zanconato F, Cordenonsi M, Piccolo S. YAP/TAZ at the roots of cancer. Cancer Cell. 2016;29:783–803.

  8. 8.

    Meng Z, Moroishi T, Guan KL. Mechanisms of Hippo pathway regulation. Genes Dev. 2016;30:1–17.

  9. 9.

    Dong J, Feldmann G, Huang J, Wu S, Zhang N, Comerford SA, et al. Elucidation of a universal size-control mechanism in Drosophila and mammals. Cell. 2007;130:1120–33.

  10. 10.

    Zhao B, Wei X, Li W, Udan RS, Yang Q, Kim J, et al. Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. Genes Dev. 2007;21:2747–61.

  11. 11.

    Goulev Y, Fauny JD, Gonzalez-Marti B, Flagiello D, Silber J, Zider A. SCALLOPED interacts with YORKIE, the nuclear effector of the hippo tumor-suppressor pathway in Drosophila. Curr Biol: CB. 2008;18:435–41.

  12. 12.

    Wu S, Liu Y, Zheng Y, Dong J, Pan D. The TEAD/TEF family protein Scalloped mediates transcriptional output of the Hippo growth-regulatory pathway. Dev Cell. 2008;14:388–98.

  13. 13.

    Zhang L, Ren F, Zhang Q, Chen Y, Wang B, Jiang J. The TEAD/TEF family of transcription factor Scalloped mediates Hippo signaling in organ size control. Dev Cell. 2008;14:377–87.

  14. 14.

    Zhao B, Ye X, Yu J, Li L, Li W, Li S, et al. TEAD mediates YAP-dependent gene induction and growth control. Genes Dev. 2008;22:1962–71.

  15. 15.

    Wang Z, Liu P, Zhou X, Wang T, Feng X, Sun YP, et al. Endothelin promotes colorectal tumorigenesis by activating YAP/TAZ. Cancer Res. 2017;77:2413–23.

  16. 16.

    Zhou D, Conrad C, Xia F, Park JS, Payer B, Yin Y, et al. Mst1 and Mst2 maintain hepatocyte quiescence and suppress hepatocellular carcinoma development through inactivation of the Yap1 oncogene. Cancer Cell. 2009;16:425–38.

  17. 17.

    Song H, Mak KK, Topol L, Yun K, Hu J, Garrett L, et al. Mammalian Mst1 and Mst2 kinases play essential roles in organ size control and tumor suppression. Proc Natl Acad Sci USA. 2010;107:1431–6.

  18. 18.

    Lu L, Li Y, Kim SM, Bossuyt W, Liu P, Qiu Q, et al. Hippo signaling is a potent in vivo growth and tumor suppressor pathway in the mammalian liver. Proc Natl Acad Sci USA. 2010;107:1437–42.

  19. 19.

    Yimlamai D, Fowl BH, Camargo FD. Emerging evidence on the role of the Hippo/YAP pathway in liver physiology and cancer. J Hepatol. 2015;63:1491–501.

  20. 20.

    Camargo FD, Gokhale S, Johnnidis JB, Fu D, Bell GW, Jaenisch R, et al. YAP1 increases organ size and expands undifferentiated progenitor cells. Curr Biol. 2007;17:2054–60.

  21. 21.

    Oh JE, Ohta T, Satomi K, Foll M, Durand G, McKay J, et al. Alterations in the NF2/LATS1/LATS2/YAP Pathway in Schwannomas. J Neuropathol Exp Neurol. 2015;74:952–9.

  22. 22.

    Baia GS, Caballero OL, Orr BA, Lal A, Ho JS, Cowdrey C, et al. Yes-associated protein 1 is activated and functions as an oncogene in meningiomas. Mol Cancer Res. 2012;10:904–13.

  23. 23.

    Bueno R, Stawiski EW, Goldstein LD, Durinck S, De Rienzo A, Modrusan Z, et al. Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations. Nat Genet. 2016;48:407–16.

  24. 24.

    Murakami H, Mizuno T, Taniguchi T, Fujii M, Ishiguro F, Fukui T, et al. LATS2 is a tumor suppressor gene of malignant mesothelioma. Cancer Res. 2011;71:873–83.

  25. 25.

    Barry ERMT, Butler BL, Shrestha K, de la Rosa R, Yan KS, et al. Restriction of intestinal stem cell expansion and the regenerative response by YAP. Nature. 2013;493:106–10.

  26. 26.

    Cottini F, Hideshima T, Xu C, Sattler M, Dori M, Agnelli L, et al. Rescue of Hippo coactivator YAP1 triggers DNA damage-induced apoptosis in hematological cancers. Nat Med. 2014;20:599–606.

  27. 27.

    Huang H, Zhang W, Pan Y, Gao Y, Deng L, Li F, et al. YAP suppresses lung squamous cell carcinoma progression via deregulation of the DNp63-GPX2 axis and ROS accumulation. Cancer Res. 2017;77:5769–81.

  28. 28.

    Moroishi T, Hayashi T, Pan WW, Fujita Y, Holt MV, Qin J, et al. The Hippo pathway kinases LATS1/2 suppress cancer immunity. Cell. 2016;167:1525–1539.e1517.

  29. 29.

    Ran FA, Hsu PD, Wright J, Agarwala V, Scott DA, Zhang F. Genome engineering using the CRISPR-Cas9 system. Nat Protoc. 2013;8:2281–308.

  30. 30.

    Sharpless NE, Sherr CJ. Forging a signature of in vivo senescence. Nat Rev Cancer. 2015;15:397–408.

  31. 31.

    Dupont S, Morsut L, Aragona M, Enzo E, Giulitti S, Cordenonsi M, et al. Role of YAP/TAZ in mechanotransduction. Nature. 2011;474:179–83.

  32. 32.

    Yuan M, Tomlinson V, Lara R, Holliday D, Chelala C, Harada T, et al. Yes-associated protein (YAP) functions as a tumor suppressor in breast. Cell Death Differ. 2008;15:1752–9.

  33. 33.

    Barreto SC, Ray A, Ag Edgar P. Biological characteristics of CCN proteins in tumor development. J BUON. 2016;21:1359–67.

  34. 34.

    Dhar G, Banerjee S, Dhar K, Tawfik O, Mayo MS, Vanveldhuizen PJ, et al. Gain of oncogenic function of p53 mutants induces invasive phenotypes in human breast cancer cells by silencing CCN5/WISP-2. Cancer Res. 2008;68:4580–7.

  35. 35.

    Ji J, Jia S, Jia Y, Ji K, Hargest R, Jiang WG. WISP-2 in human gastric cancer and its potential metastatic suppressor role in gastric cancer cells mediated by JNK and PLC-gamma pathways. Br J Cancer. 2015;113:921–33.

  36. 36.

    Ferraro A, Schepis F, Leone V, Federico A, Borbone E, Pallante P, et al. Tumor suppressor role of the CL2/DRO1/CCDC80 gene in thyroid carcinogenesis. J Clin Endocrinol Metab. 2013;98:2834–43.

  37. 37.

    Herbst A, Bayer C, Wypior C, Kolligs FT. DRO1 sensitizes colorectal cancer cells to receptor-mediated apoptosis. Oncol Lett. 2011;2:981–4.

  38. 38.

    Bommer GT, Jager C, Durr EM, Baehs S, Eichhorst ST, Brabletz T, et al. DRO1, a gene down-regulated by oncogenes, mediates growth inhibition in colon and pancreatic cancer cells. J Biol Chem. 2005;280:7962–75.

  39. 39.

    Jiao SLC, Hao Q, Miao H, Zhang L, Li L, Zhou Z. VGLL4 targets a TCF4–TEAD4 complex to coregulate Wnt and Hippo signalling in colorectal cancer. Nat Commun. 2017;8:14058.

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Acknowledgements

We thank Zhipeng Meng, Rui Chen, Shenghong Ma, Zhengming Wu, Kimberly C, Lin and Min Luo for technical assistance; JiaYu Chen and Xiangdong Fu for help in bioinformatics analysis. This work was supported by grants from the National Institutes of Health (CA196878, CA217642, and GM51586) to K.L.G. This study was supported by grants from National Natural Science Foundation of China (31871402, 81402162), and the Natural Science Foundation of Zhejiang Province (LY17H160060) to W.W.P.

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Correspondence to Wei-Wei Pan or Kun-Liang Guan.

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Conflict of interest

K-LG is a co-founder and has an equity interest in Vivace Therapeutics, Inc. The terms of this arrangement have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies.

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