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

Abstract

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.

• Authors: 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
• Journal: Cancer cell (Cancer Cell) Vol. 29 Issue 6 Pg. 874-888 (06 13 2016) ISSN: 1878-3686 [Electronic] United States
• PMID: 27300436 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 Elsevier Inc. All rights reserved.

Chemical References

• DGCR8 protein, human
• Histone Deacetylase Inhibitors
• MIRN128 microRNA, human
• MicroRNAs
• RNA-Binding Proteins
• Small Molecule Libraries
• TP53 protein, human
• TP63 protein, human
• Transcription Factors
• Tumor Suppressor Protein p53
• Tumor Suppressor Proteins
• mirnlet7 microRNA, human

Topics

• Animals
• Carcinoma, Squamous Cell (drug therapy, genetics)
• Cell Line, Tumor
• Drug Resistance, Neoplasm
• Gene Expression Regulation, Neoplastic
• Histone Deacetylase Inhibitors (administration & dosage, pharmacology)
• Humans
• Lymphoma (drug therapy, genetics)
• Mice
• MicroRNAs (genetics)
• RNA-Binding Proteins (genetics)
• Small Molecule Libraries (administration & dosage, pharmacology)
• Transcription Factors (genetics)
• Tumor Suppressor Protein p53 (genetics)
• Tumor Suppressor Proteins (genetics)
• Xenograft Model Antitumor Assays