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ΔNp63/DGCR8-Dependent MicroRNAs Mediate Therapeutic Efficacy of HDAC Inhibitors in Cancer

2016; Cell Press; Volume: 29; Issue: 6 Linguagem: Inglês

10.1016/j.ccell.2016.04.016

1878-3686

Marco Napoli, Avinashnarayan Venkatanarayan, Payal Raulji, Brooke A. Meyers, William Norton, Lingegowda S. Mangala, Anil K. Sood, Cristian Rodriguez‐Aguayo, Gabriel López-Berestein, Harina Vin, Madeleine Duvic, Michael Tetzlaff, Jonathan L. Curry, Alain H. Rook, Hussein A. Abbas, Cristian Coarfa, Preethi H. Gunaratne, Kenneth Y. Tsai, Elsa R. Flores,

Protein Degradation and Inhibitors

ΔNp63 is an oncogenic member of the p53 family and acts to inhibit the tumor-suppressive activities of the p53 family. By performing a chemical library screen, we identified histone deacetylase inhibitors (HDACi) as agents reducing ΔNp63 protein stability through the E3 ubiquitin ligase, Fbw7. ΔNp63 inhibition decreases the levels of its transcriptional target, DGCR8, and the maturation of let-7d and miR-128, which we found to be critical for HDACi function in vitro and in vivo. Our work identified Fbw7 as a predictive marker for HDACi response in squamous cell carcinomas and lymphomas, and unveiled let-7d and miR-128 as specific targets to bypass tumor resistance to HDACi treatment.