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Systematic characterization of chromatin modifying enzymes identifies KDM3B as a critical regulator in castration resistant prostate cancer
- Source :
- Oncogene
- Publication Year :
- 2019
-
Abstract
- 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.<br />Scientific and Technological Research Council of Turkey (TÜBİTAK); Royal Society Newton Advanced Fellowship; Wellcome Trust Core Award; Royal Society Dorothy Hodgkin Fellowship; Cancer Research UK Programme
- Subjects :
- 0301 basic medicine
Male
Cancer Research
Jumonji Domain-Containing Histone Demethylases
Cellular differentiation
Methylation
Article
Transcriptome
Androgen deprivation therapy
Histones
03 medical and health sciences
Prostate cancer
0302 clinical medicine
Cell Line, Tumor
Histone methylation
Histone post-translational modifications
Genetics
medicine
Humans
Molecular Biology
Cell biology
Genetics and heredity
Carcinoma-cell line
Androgen-receptor
H3K9 methylation
Tumor growth
Demethylase
Progression
Proliferation
Transcription
Expression
Protein
biology
Arginase
Biochemistry and molecular biology
Oncology
Gene Expression Profiling
Cancer
medicine.disease
3. Good health
Gene Expression Regulation, Neoplastic
Histone Code
Prostatic Neoplasms, Castration-Resistant
030104 developmental biology
Histone
030220 oncology & carcinogenesis
RNAi
PC-3 Cells
biology.protein
Cancer research
Epigenetics
Oxidoreductases
Protein Processing, Post-Translational
Subjects
Details
- Language :
- English
- ISSN :
- 14765594 and 09509232
- Database :
- OpenAIRE
- Journal :
- Oncogene
- Accession number :
- edsair.doi.dedup.....1c087a5741d121d9f36fdc5a3df587a9