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Lookup NU author(s): Dr Hilal SaracORCiD, Professor Akane Kawamura
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Androgen deprivation therapy (ADT) is the standard care for prostate cancer (PCa) patients who fail surgery or radiotherapy. While initially effective, the cancer almost always recurs as a more aggressive castration resistant prostate cancer (CRPC). Previous studies have demonstrated that chromatin modifying enzymes can play a critical role in the conversion to CRPC. However, only a handful of these potential pharmacological targets have been tested. Therefore, in this study, we conducted a focused shRNA screen of chromatin modifying enzymes previously shown to be involved in cellular differentiation. We found that altering the balance between histone methylation and demethylation impacted growth and proliferation. Of all genes tested, KDM3B, a histone H3K9 demethylase, was found to have the most antiproliferative effect. These results were phenocopied with a KDM3B CRISPR/Cas9 knockout. When tested in several PCa cell lines, the decrease in proliferation was remarkably specific to androgen-independent cells. Genetic rescue experiments showed that only the enzymatically active KDM3B could recover the phenotype. Surprisingly, despite the decreased proliferation of androgen-independent cell no alterations in the cell cycle distribution were observed following KDM3B knockdown. Whole transcriptome analyses revealed changes in the gene expression profile following loss of KDM3B, including downregulation of metabolic enzymes such as ARG2 and RDH11. Metabolomic analysis of KDM3B knockout showed a decrease in several critical amino acids. Overall, our work reveals, for the first time, the specificity and the dependence of KDM3B in CRPC proliferation.
Author(s): Sarac H, Morova T, Pires E, McCullagh J, Kaplan A, Cingoz A, Bagci-Onder T, Onder T, Kawamura A, Lack NA
Publication type: Article
Publication status: Published
Journal: Oncogene
Year: 2020
Volume: 39
Pages: 2187–2201
Print publication date: 05/03/2020
Online publication date: 10/12/2019
Acceptance date: 11/11/2019
Date deposited: 08/01/2020
ISSN (print): 0950-9232
ISSN (electronic): 1476-5594
Publisher: Nature Publishing Group
URL: https://doi.org/10.1038/s41388-019-1116-8
DOI: 10.1038/s41388-019-1116-8
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