Abstract
Over the past decades, the Hippo has been established as a crucial pathway involved in organ size control and cancer suppression. Dysregulation of Hippo signaling and hyperactivation of its downstream effector YAP are frequently associated with various human cancers. However, the underlying significance of such YAP activation in cancer development and therapy has not been fully characterized. In this study, we reported that the Hippo signaling deficiency can lead to a YAP-dependent oncogene addiction for cancer cells. Through a clinical compound library screen, we identified histone deacetylase (HDAC) inhibitors as putative inhibitors to suppress YAP expression. Importantly, HDAC inhibitors specifically targeted the viability and xenograft tumor growth for the cancer cells in which YAP is constitutively active. Taken together, our results not only establish an active YAP-induced oncogene addiction in cancer cells, but also lay the foundation to develop targeted therapies for the cancers with Hippo dysfunction and YAP activation.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.
Weinstein IB, Joe A. Oncogene addiction. Cancer Res. 2008;68:3077–80. discussion 3080
Sharma SV, Settleman J. Oncogene addiction: setting the stage for molecularly targeted cancer therapy. Genes Dev. 2007;21:3214–31.
Pagliarini R, Shao W, Sellers WR. Oncogene addiction: pathways of therapeutic response, resistance, and road maps toward a cure. EMBO Rep. 2015;16:280–96.
Pan D. The Hippo signaling pathway in development and cancer. Dev Cell. 2010;19:491–505.
Yu FX, Zhao B, Guan KL. Hippo pathway in organ size control, tissue homeostasis, and cancer. Cell. 2015;163:811–28.
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.
Meng Z, Moroishi T, Mottier-Pavie V, Plouffe SW, Hansen CG, Hong AW, et al. MAP4K family kinases act in parallel to MST1/2 to activate LATS1/2 in the Hippo pathway. Nat Commun. 2015;6:8357.
Zheng Y, Wang W, Liu B, Deng H, Uster E, Pan D. Identification of Happyhour/MAP4K as alternative Hpo/Mst-like kinases in the Hippo kinase cascade. Dev Cell. 2015;34:642–55.
Li Q, Li S, Mana-Capelli S, Roth Flach RJ, Danai LV, Amcheslavsky A, et al. The conserved misshapen-warts-Yorkie pathway acts in enteroblasts to regulate intestinal stem cells in Drosophila. Dev Cell. 2014;31:291–304.
Li S, Cho YS, Yue T, Ip YT, Jiang J. Overlapping functions of the MAP4K family kinases Hppy and Msn in Hippo signaling. Cell Discov. 2015;1:15038.
Plouffe SW, Meng Z, Lin KC, Lin B, Hong AW, Chun JV, et al. Characterization of Hippo pathway components by gene inactivation. Mol Cell. 2016;64:993–1008.
Petrilli AM, Fernandez-Valle C. Role of Merlin/NF2 inactivation in tumor biology. Oncogene. 2016;35:537–48.
Zanconato F, Cordenonsi M, Piccolo S. YAP/TAZ at the roots of cancer. Cancer Cell. 2016;29:783–803.
Bonilla X, Parmentier L, King B, Bezrukov F, Kaya G, Zoete V, et al. Genomic analysis identifies new drivers and progression pathways in skin basal cell carcinoma. Nat Genet. 2016;48:398–406.
Feng X, Degese MS, Iglesias-Bartolome R, Vaque JP, Molinolo AA, Rodrigues M, et al. Hippo-independent activation of YAP by the GNAQ uveal melanoma oncogene through a trio-regulated rho GTPase signaling circuitry. Cancer Cell. 2014;25:831–45.
Yu FX, Luo J, Mo JS, Liu G, Kim YC, Meng Z, et al. Mutant Gq/11 promote uveal melanoma tumorigenesis by activating YAP. Cancer Cell. 2014;25:822–30.
Shao DD, Xue W, Krall EB, Bhutkar A, Piccioni F, Wang X, et al. KRAS and YAP1 converge to regulate EMT and tumor survival. Cell. 2014;158:171–84.
Kapoor A, Yao W, Ying H, Hua S, Liewen A, Wang Q, et al. Yap1 activation enables bypass of oncogenic Kras addiction in pancreatic cancer. Cell. 2014;158:185–97.
Plouffe SW, Lin KC, Moore JL, Tan FE, Ma S, Ye Z, et al. The Hippo pathway effector proteins YAP and TAZ have both distinct and overlapping functions in the cell. J Biol Chem. 2018;293:11230–11240.
Wang W, Li N, Li X, Tran MK, Han X, Chen J. Tankyrase inhibitors target YAP by stabilizing angiomotin family proteins. Cell Rep. 2015;13:524–32.
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.
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–.e17.
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.
Zhang N, Bai H, David KK, Dong J, Zheng Y, Cai J, et al. The Merlin/NF2 tumor suppressor functions through the YAP oncoprotein to regulate tissue homeostasis in mammals. Dev Cell. 2010;19:27–38.
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.
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.
Zhang WQ, Dai YY, Hsu PC, Wang H, Cheng L, Yang YL, et al. Targeting YAP in malignant pleural mesothelioma. J Cell Mol Med. 2017;21:2663–76.
Mizuno T, Murakami H, Fujii M, Ishiguro F, Tanaka I, Kondo Y, et al. YAP induces malignant mesothelioma cell proliferation by upregulating transcription of cell cycle-promoting genes. Oncogene. 2012;31:5117–22.
Jung DE, Park SB, Kim K, Kim C, Song SY. CG200745, an HDAC inhibitor, induces anti-tumour effects in cholangiocarcinoma cell lines via miRNAs targeting the Hippo pathway. Sci Rep. 2017;7:10921.
Li Y, Seto E.HDACs and HDAC inhibitors in cancer development and therapy.Cold Spring Harb Perspect Med. 2016;6:pii: a026831
Mottamal M, Zheng SL, Huang TL, Wang GD. Histone deacetylase inhibitors in clinical studies as templates for new anticancer agents. Molecules. 2015;20:3898–941.
Wang T, Wei JJ, Sabatini DM, Lander ES. Genetic screens in human cells using the CRISPR-Cas9 system. Science. 2014;343:80–4.
Wang W, Chen L, Ding Y, Jin J, Liao K. Centrosome separation driven by actin-microfilaments during mitosis is mediated by centrosome-associated tyrosine-phosphorylated cortactin. J Cell Sci. 2008;121:1334–43.
Acknowledgements
We thank Drs. Steven H Lin and Junjie Chen (MD Anderson Cancer Center) for the clinical compound library. WW is a recipient of an American Association for Cancer Research Career Development Award for Translational Breast Cancer Research supported by the Breast Cancer Research Foundation (16-20-26-WANG). This work was supported by University of California, Irvine Chao Family Comprehensive Cancer Center (Pilot Project 2018) and in part by a NIH grant (R01 GM126048) and a Research Scholar Grant (RSG-18-009-01-CCG) from the American Cancer Society to WW.
Author contributions
WW conceived and supervised study. HH and WW designed the experiments and analyzed the data. HH and BY performed all the experiments with the assistance from HJN, JY, YZ, KLN, ATB and TKM. WW wrote the manuscript.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Electronic supplementary material
Rights and permissions
About this article
Cite this article
Han, H., Yang, B., Nakaoka, H.J. et al. Hippo signaling dysfunction induces cancer cell addiction to YAP. Oncogene 37, 6414–6424 (2018). https://doi.org/10.1038/s41388-018-0419-5
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41388-018-0419-5
This article is cited by
-
Hippo pathway dysregulation in gastric cancer: from Helicobacter pylori infection to tumor promotion and progression
Cell Death & Disease (2023)
-
The role of YAP1 in liver cancer stem cells: proven and potential mechanisms
Biomarker Research (2022)
-
Hippo pathway regulation by phosphatidylinositol transfer protein and phosphoinositides
Nature Chemical Biology (2022)
-
Targeting FAK in anticancer combination therapies
Nature Reviews Cancer (2021)
-
KLF4 initiates sustained YAP activation to promote renal fibrosis in mice after ischemia-reperfusion kidney injury
Acta Pharmacologica Sinica (2021)