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

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

doi:10.1016/j.ccell.2016.04.016

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

Cancer Cell. 2016 Jun 13;29(6):874-888. doi: 10.1016/j.ccell.2016.04.016.

Authors

Marco Napoli¹, Avinashnarayan Venkatanarayan², Payal Raulji¹, Brooke A Meyers¹, William Norton³, Lingegowda S Mangala⁴, Anil K Sood⁴, Cristian Rodriguez-Aguayo⁵, Gabriel Lopez-Berestein⁵, Harina Vin⁶, Madeleine Duvic⁶, Michael B Tetzlaff⁷, Jonathan L Curry⁷, Alain H Rook⁸, Hussein A Abbas¹, Cristian Coarfa⁹, Preethi H Gunaratne¹⁰, Kenneth Y Tsai¹¹, Elsa R Flores¹²

Affiliations

¹ Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
² Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA; Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
³ Department of Veterinary Medicine and Surgery, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
⁴ Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA; Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
⁵ Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA; Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
⁶ Department of Dermatology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
⁷ Department of Dermatology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA; Department of Pathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
⁸ Department of Dermatology, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁹ Department of Molecular and Cellular Biology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
¹⁰ Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USA.
¹¹ Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA; Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA; Department of Dermatology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
¹² Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA; Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA; Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. Electronic address: elsaflores@mdanderson.org.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding