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

Oncogene volume 38, pages 2595–2610 (2019)Cite this article

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

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

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

    PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

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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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  1. Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA, 92093, USA

    Wei-Wei Pan, Toshiro Moroishi, Ja Hyun Koo & Kun-Liang Guan

  2. School of Medicine, Jiaxing University, 314001, Jiaxing, China

    Wei-Wei Pan

  3. Department of Molecular Enzymology and Center for Metabolic Regulation of Healthy Aging, Faculty of Life Sciences, Kumamoto University, Kumamoto, 860-8556, Japan

    Toshiro Moroishi

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

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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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Pan, WW., Moroishi, T., Koo, J.H. et al. Cell type-dependent function of LATS1/2 in cancer cell growth. Oncogene 38, 2595–2610 (2019). https://doi.org/10.1038/s41388-018-0610-8

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