Human Ex Vivo Prostate Tissue Model System Identifies ING3 As an Oncoprotein

Overview

Journal Br J Cancer

Specialty Oncology

Date 2018 Jan 31

PMID 29381681

Citations 17

Authors

Urszula L McClurg

Arash Nabbi

Charles Ricordel

Svitlana Korolchuk

Stuart McCracken

Rakesh Heer

Laura Wilson

Lisa M Butler

Bronwyn Kate Irving-Hooper

Remy Pedeux

Craig N Robson

Karl T Riabowol

Olivier Binda

Affiliations

Soon will be listed here.

Abstract

Background: Although the founding members of the INhibitor of Growth (ING) family of histone mark readers, ING1 and ING2, were defined as tumour suppressors in animal models, the role of other ING proteins in cellular proliferation and cancer progression is unclear.

Methods: We transduced ex vivo benign prostate hyperplasia tissues with inducible lentiviral particles to express ING proteins. Proliferation was assessed by H3S10 immunohistochemistry (IHC). The expression of ING3 was assessed by IHC on a human prostate cancer tissue microarray (TMA). Gene expression was measured by DNA microarray and validated by real-time qPCR.

Results: We found that ING3 stimulates cellular proliferation in ex vivo tissues, suggesting that ING3 could be oncogenic. Indeed, ING3 overexpression transformed normal human dermal fibroblasts. We observed elevated levels of ING3 in prostate cancer samples, which correlated with poorer patient survival. Consistent with an oncogenic role, gene-silencing experiments revealed that ING3 is required for the proliferation of breast, ovarian, and prostate cancer cells. Finally, ING3 controls the expression of an intricate network of cell cycle genes by associating with chromatin modifiers and the H3K4 mark at transcriptional start sites.

Conclusions: Our investigations create a shift in the prevailing view that ING proteins are tumour suppressors and redefine ING3 as an oncoprotein.

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The TUDOR domain of SMN is an H3K79 histone mark reader.

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