TY - JOUR
T1 - Rescue of Hippo coactivator YAP1 triggers DNA damage-induced apoptosis in hematological cancers
AU - Cottini, Francesca
AU - Hideshima, Teru
AU - Xu, Chunxiao
AU - Sattler, Martin
AU - Dori, Martina
AU - Agnelli, Luca
AU - Ten Hacken, Elisa
AU - Bertilaccio, Maria Teresa
AU - Antonini, Elena
AU - Neri, Antonino
AU - Ponzoni, Maurilio
AU - Marcatti, Magda
AU - Richardson, Paul G.
AU - Carrasco, Ruben
AU - Kimmelman, Alec C.
AU - Wong, Kwok Kin
AU - Caligaris-Cappio, Federico
AU - Blandino, Giovanni
AU - Kuehl, W. Michael
AU - Anderson, Kenneth C.
AU - Tonon, Giovanni
N1 - Funding Information:
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.
PY - 2014/6
Y1 - 2014/6
N2 - 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.
AB - 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.
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U2 - 10.1038/nm.3562
DO - 10.1038/nm.3562
M3 - Article
C2 - 24813251
AN - SCOPUS:84902083075
SN - 1078-8956
VL - 20
SP - 599
EP - 606
JO - Nature medicine
JF - Nature medicine
IS - 6
ER -