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

Publication date: 13 June 2016
Source:Cancer Cell, Volume 29, Issue 6
Author(s): Marco Napoli, Avinashnarayan Venkatanarayan, Payal Raulji, Brooke A. Meyers, William Norton, Lingegowda S. Mangala, Anil K. Sood, Cristian Rodriguez-Aguayo, Gabriel Lopez-Berestein, Harina Vin, Madeleine Duvic, Michael B. Tetzlaff, Jonathan L. Curry, Alain H. Rook, Hussein A. Abbas, Cristian Coarfa, Preethi H. Gunaratne, Kenneth Y. Tsai, Elsa R. Flores
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.

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Teaser

Napoli et al. show that HDAC inhibitors (HDACi) target the ΔNp63/DGCR8 axis to inhibit ΔNp63-dependent tumors, especially those lacking functional p53. ΔNp63 inhibition decreases DGCR8 expression and maturation of let-7d and miR-128. They also identify Fbw7 level as a predictive marker for HDACi response.


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