Oncogene-induced DNA damage elicits genomic instability in epithelial cancer cells, but apoptosis is blocked through inactivation of the tumor suppressor p53. In hematological cancers, the relevance of ongoing DNA damage and the mechanisms by which apoptosis is suppressed are largely unknown. We found pervasive DNA damage in hematologic malignancies, including multiple myeloma, lymphoma and leukemia, which leads to activation of a p53-independent, proapoptotic network centered on nuclear relocalization of ABL1 kinase. Although nuclear ABL1 triggers cell death through its interaction with the Hippo pathway coactivator YAP1 in normal cells, we show that low YAP1 levels prevent nuclear ABL1-induced apoptosis in these hematologic malignancies. YAP1 is under the control of a serine-threonine kinase, STK4. Notably, genetic inactivation of STK4 restores YAP1 levels, triggering cell death in vitro and in vivo. Our data therefore identify a new synthetic-lethal strategy to selectively target cancer cells presenting with endogenous DNA damage and low YAP1 levels.
This is a preview of subscription content
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Halazonetis, T.D., Gorgoulis, V.G. & Bartek, J. An oncogene-induced DNA damage model for cancer development. Science 319, 1352–1355 (2008).
Boehrer, S. et al. Suppression of the DNA damage response in acute myeloid leukemia versus myelodysplastic syndrome. Oncogene 28, 2205–2218 (2009).
Walters, D.K. et al. Evidence for ongoing DNA damage in multiple myeloma cells as revealed by constitutive phosphorylation of H2AX. Leukemia 25, 1344–1353 (2011).
Xu-Monette, Z.Y. et al. Dysfunction of the TP53 tumor suppressor gene in lymphoid malignancies. Blood 119, 3668–3683 (2012).
Chapman, M.A. et al. Initial genome sequencing and analysis of multiple myeloma. Nature 471, 467–472 (2011).
Baskaran, R. et al. Ataxia telangiectasia mutant protein activates c-Abl tyrosine kinase in response to ionizing radiation. Nature 387, 516–519 (1997).
Kharbanda, S. et al. Activation of the c-Abl tyrosine kinase in the stress response to DNA-damaging agents. Nature 376, 785–788 (1995).
Shafman, T. et al. Interaction between ATM protein and c-Abl in response to DNA damage. Nature 387, 520–523 (1997).
Yuan, Z.M. et al. Regulation of DNA damage–induced apoptosis by the c-Abl tyrosine kinase. Proc. Natl. Acad. Sci. USA 94, 1437–1440 (1997).
Yuan, Z.M. et al. Role for c-Abl tyrosine kinase in growth arrest response to DNA damage. Nature 382, 272–274 (1996).
Gorgoulis, V.G. et al. Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Nature 434, 907–913 (2005).
Bartkova, J. et al. DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature 434, 864–870 (2005).
Brown, L. & McCarthy, N. DNA repair. A sense-abl response? Nature 387, 450–451 (1997).
Yoshida, K., Yamaguchi, T., Natsume, T., Kufe, D. & Miki, Y. JNK phosphorylation of 14-3-3 proteins regulates nuclear targeting of c-Abl in the apoptotic response to DNA damage. Nat. Cell Biol. 7, 278–285 (2005).
Hickson, I. et al. Identification and characterization of a novel and specific inhibitor of the ataxia-telangiectasia mutated kinase ATM. Cancer Res. 64, 9152–9159 (2004).
Bennett, B.L. et al. SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase. Proc. Natl. Acad. Sci. USA 98, 13681–13686 (2001).
White, E. & Prives, C. DNA damage enables p73. Nature 399, 734–735, 737 (1999).
Sudol, M. Yes-associated protein (YAP65) is a proline-rich phosphoprotein that binds to the SH3 domain of the Yes proto-oncogene product. Oncogene 9, 2145–2152 (1994).
Levy, D., Adamovich, Y., Reuven, N. & Shaul, Y. Yap1 phosphorylation by c-Abl is a critical step in selective activation of proapoptotic genes in response to DNA damage. Mol. Cell 29, 350–361 (2008).
Levy, D., Adamovich, Y., Reuven, N. & Shaul, Y. The Yes-associated protein 1 stabilizes p73 by preventing Itch-mediated ubiquitination of p73. Cell Death Differ. 14, 743–751 (2007).
Keats, J.J. et al. Promiscuous mutations activate the noncanonical NF-κB pathway in multiple myeloma. Cancer Cell 12, 131–144 (2007).
Annunziata, C.M. et al. Frequent engagement of the classical and alternative NF-κB pathways by diverse genetic abnormalities in multiple myeloma. Cancer Cell 12, 115–130 (2007).
Carrasco, D.R. et al. High-resolution genomic profiles define distinct clinico-pathogenetic subgroups of multiple myeloma patients. Cancer Cell 9, 313–325 (2006).
Walker, B.A. et al. A compendium of myeloma-associated chromosomal copy number abnormalities and their prognostic value. Blood 116, e56–e65 (2010).
Basu, S., Totty, N.F., Irwin, M.S., Sudol, M. & Downward, J. Akt phosphorylates the Yes-associated protein, YAP, to induce interaction with 14-3-3 and attenuation of p73-mediated apoptosis. Mol. Cell 11, 11–23 (2003).
Strano, S. et al. Physical interaction with Yes-associated protein enhances p73 transcriptional activity. J. Biol. Chem. 276, 15164–15173 (2001).
Strano, S. et al. The transcriptional coactivator Yes-associated protein drives p73 gene-target specificity in response to DNA Damage. Mol. Cell 18, 447–459 (2005).
Lapi, E. et al. PML, YAP, and p73 are components of a proapoptotic autoregulatory feedback loop. Mol. Cell 32, 803–814 (2008).
Zhou, D. et al. Mst1 and Mst2 maintain hepatocyte quiescence and suppress hepatocellular carcinoma development through inactivation of the Yap1 oncogene. Cancer Cell 16, 425–438 (2009).
Zhou, D. et al. Mst1 and Mst2 protein kinases restrain intestinal stem cell proliferation and colonic tumorigenesis by inhibition of Yes-associated protein (Yap) overabundance. Proc. Natl. Acad. Sci. USA 108, E1312–E1320 (2011).
Creasy, C.L., Ambrose, D.M. & Chernoff, J. The Ste20-like protein kinase, Mst1, dimerizes and contains an inhibitory domain. J. Biol. Chem. 271, 21049–21053 (1996).
Kaelin, W.G. Jr. The concept of synthetic lethality in the context of anticancer therapy. Nat. Rev. Cancer 5, 689–698 (2005).
Pan, D. The Hippo signaling pathway in development and cancer. Dev. Cell 19, 491–505 (2010).
Bertini, E., Oka, T., Sudol, M., Strano, S. & Blandino, G. YAP: at the crossroad between transformation and tumor suppression. Cell Cycle 8, 49–57 (2009).
Harvey, K.F., Zhang, X. & Thomas, D.M. The Hippo pathway and human cancer. Nat. Rev. Cancer 13, 246–257 (2013).
Reuven, N., Adler, J., Meltser, V. & Shaul, Y. The Hippo pathway kinase Lats2 prevents DNA damage–induced apoptosis through inhibition of the tyrosine kinase c-Abl. Cell Death Differ. 20, 1330–1340 (2013).
Tschop, K. et al. A kinase shRNA screen links LATS2 and the pRB tumor suppressor. Genes Dev. 25, 814–830 (2011).
Piccolo, S., Cordenonsi, M. & Dupont, S. Molecular pathways: YAP and TAZ take center stage in organ growth and tumorigenesis. Clin. Cancer Res. 19, 4925–4930 (2013).
We thank M. Sudol (Mount Sinai School of Medicine) for the eGFP-YAP1 construct, W. Hahn (Dana-Farber Cancer Institute) for pLKO.1 shRNA lentiviral vectors and S. Rosen (Northwestern University) and R. Burger (University of Kiel) for MM.1R and INA-6 MM cells. We also thank E. Di Cairano and L. Spagnuolo for immunohistochemical stains, F. Ghini and A.M. Gasparri for technical help, the Dana-Farber Cancer Institute Flow cytometry facility, D. Kufe and F. Bernassola for insightful suggestions, C. Brennan for the bioinformatics analysis and members of the Anderson and Tonon lab for sharing reagents and critical reading of the manuscript. W.M.K. is supported by the Intramural Research Program of the US National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research. This work was supported by Fondazione CARIPLO, a Marie Curie International Reintegration Grant and the Associazione Italiana per la Ricerca sul Cancro (AIRC; AIRC Special Program Molecular Clinical Oncology, 5 per mille no. 9980 to A.N. and Investigator Grants and Special Program Molecular Clinical Oncology, 5 per mille no. 9965 to G.T.) (G.T.). K.C.A. is an American Cancer Society Clinical Research Professor and is supported by NIH grants NIH SPORE P50 100707, PO-1 78378 and RO-1 50947.
The authors declare no competing financial interests.
About this article
Cite this article
Cottini, F., Hideshima, T., Xu, C. et al. Rescue of Hippo coactivator YAP1 triggers DNA damage–induced apoptosis in hematological cancers. Nat Med 20, 599–606 (2014). https://doi.org/10.1038/nm.3562
Preclinical validation and phase I trial of 4-hydroxysalicylanilide, targeting ribonucleotide reductase mediated dNTP synthesis in multiple myeloma
Journal of Biomedical Science (2022)
Transcriptional repression of estrogen receptor alpha by YAP reveals the Hippo pathway as therapeutic target for ER+ breast cancer
Nature Communications (2022)
Nature Communications (2022)
Medical Oncology (2022)
An overview of the crosstalk between YAP and cGAS-STING signaling in non-small cell lung cancer: it takes two to tango
Clinical and Translational Oncology (2022)