Journal
CANCER RESEARCH
Volume 78, Issue 16, Pages 4704-4715Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-18-0399
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Funding
- NIH [R01CA172136, R01CA203028, U19AI068021, R01CA215481, R01CA149442, R01CA217141]
- [P30CA047904]
- NATIONAL CANCER INSTITUTE [R01CA215481, R01CA217141, R01CA172136, P30CA047904, R01CA149442, R01CA203028] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [U19AI068021] Funding Source: NIH RePORTER
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Mcl-1, a prosurvival Bcl-2 family protein, is frequently overexpressed in cancer cells and plays a critical role in therapeutic resistance. It is well known that anticancer agents induce phosphorylation of Mcl-1, which promotes its binding to E3 ubiquitin ligases and subsequent proteasomal degradation and apoptosis. However, other functions of Mcl-1 phosphorylation in cancer cell death have not been well characterized. In this study, we show in colon cancer cells that histone deacetylase inhibitors (HDACi) induce GSK3 beta-dependent Mcl-1 phosphorylation, but not degradation or downregulation. The in vitro and in vivo anticancer effects of HDACi were dependent onMcl-1 phosphorylation and were blocked by genetic knock-in of a Mcl-1 phosphorylation site mutant. Phosphorylation-dead Mcl-1 maintained cell survival by binding and sequestering BH3-only Bcl-2 family proteins PUMA, Bim, and Noxa, which were upregulated and necessary for apoptosis induction by HDACi. Resistance to HDACi mediated by phosphorylation-dead Mcl-1 was reversed by small-molecule Mcl-1 inhibitors that liberated BH3-only proteins. These results demonstrate a critical role of Mcl-1 phosphorylation in mediating HDACi sensitivity through a novel and degradation-independent mechanism. These results provide new mechanistic insights on how Mcl-1 maintains cancer cell survival and suggest that Mcl-1-targeting agents are broadly useful for overcoming therapeutic resistance in cancer cells. Significance: These findings present a novel degradation-independent function of Mcl-1 phosphorylation in anticancer therapy that could be useful for developing new Mcl-1-targeting agents to overcome therapeutic resistance. (C) 2018 AACR.
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