Control of Histone H3 Lysine 9 (H3K9) Methylation State via Cooperative Two-step Demethylation by Jumonji Domain Containing 1A (JMJD1A) Homodimer

Goda, Satoshi; Isagawa, Takayuki; Chikaoka, Yoko; Kawamura, Takeshi; Aburatani, Hiroyuki

doi:10.1074/jbc.m113.492595

Cited by 29 publications

(21 citation statements)

References 50 publications

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“…Overall, knock down of methylation related enzymes appeared to enhance proliferation while loss of demethylases, in particular the H3K9 demethylases KDM4s/ KDM3s, decreased growth in LNCaP-abl. Importantly, this was not due to shRNA off-target effects as a similar phenotype with both different shRNA and CRISPR/Cas9 was [14,53]. Overexpression of ΔZF KDM3B may thus inactivate the endogenous KDM3B.…”

Section: Discussionmentioning

confidence: 91%

Systematic characterization of chromatin modifying enzymes identifies KDM3B as a critical regulator in castration resistant prostate cancer

et al. 2019

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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.

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Section: Discussionmentioning

confidence: 91%

Systematic characterization of chromatin modifying enzymes identifies KDM3B as a critical regulator in castration resistant prostate cancer

et al. 2019

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“…JMJD1A regulates gene expression through H3K9 demethylation ( 1 , 2 ). To assess global gene regulation by JMJD1A in an effort to identify how it regulates proliferation or survival of prostate cancer cells, we performed array-based gene expression analyses of Rv1 cells expressing JMJD1A shRNA.…”

Section: Resultsmentioning

confidence: 99%

Regulation of c-Myc expression by the histone demethylase JMJD1A is essential for prostate cancer cell growth and survival

et al. 2015

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The histone demethylase JMJD1A, which controls gene expression by epigenetic regulation of H3K9 methylation marks, functions in diverse activities, including spermatogenesis, metabolism, and stem cell self-renewal and differentiation. Here, we found that JMJD1A knockdown in prostate cancer cells antagonizes their proliferation and survival. Profiling array analyses revealed that JMJD1A-dependent genes function in cellular growth, proliferation and survival, and implicated that the c-Myc transcriptional network is de-regulated following JMJD1A inhibition. Biochemical analyses confirmed that JMJD1A enhances c-Myc transcriptional activity by upregulating c-Myc expression levels. Mechanistically, JMJD1A activity promoted recruitment of androgen receptor (AR) to the c-Myc gene enhancer and induced H3K9 demethylation, increasing AR-dependent transcription of c-Myc mRNA. In parallel, we found that JMJD1A regulated c-Myc stability, likely by inhibiting HUWE1, an E3 ubiquitin ligase known to target degradation of several substrates including c-Myc. JMJD1A (wild-type or mutant lacking histone demethylase activity) bound to HUWE1, attenuated HUWE1-dependent ubiquitination and subsequent degradation of c-Myc, increasing c-Myc protein levels. Furthermore, c-Myc knockdown in prostate cancer cells phenocopied effects of JMJD1A knockdown, and c-Myc re-expression in JMJD1A-knockdown cells partially rescued prostate cancer cell growth in vitro and in vivo. c-Myc protein levels were positively correlated with those of JMJD1A in a subset of human prostate cancer specimens. Collectively, our findings identify a critical role for JMJD1A in regulating proliferation and survival of prostate cancer cells by controlling c-Myc expression at transcriptional and post-translational levels.

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“…A recent study revealed that KDM3A was distinct from other Jumonji C family members in both its structure and function. KDM3A forms a homodimer through its catalytic domains, and catalyses removal of H3K9 methylation via a two-step process in which two active sites of the dimer are crucial for the enzymatic activity 51 . This reaction mechanism is totally different from catalytic processes of other JumonjiC H3K9 demethylases such as PHF8 and KIAA1718, which neither form a homodimer nor catalyse successive two-step methylation 52 .…”

Section: Discussionmentioning

confidence: 99%

The KDM3A–KLF2–IRF4 axis maintains myeloma cell survival

et al. 2016

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KDM3A is implicated in tumorigenesis; however, its biological role in multiple myeloma (MM) has not been elucidated. Here we identify KDM3A–KLF2–IRF4 axis dependence in MM. Knockdown of KDM3A is toxic to MM cells in vitro and in vivo. KDM3A maintains expression of KLF2 and IRF4 through H3K9 demethylation, and knockdown of KLF2 triggers apoptosis. Moreover, KLF2 directly activates IRF4 and IRF4 reciprocally upregulates KLF2, forming a positive autoregulatory circuit. The interaction of MM cells with bone marrow milieu mediates survival of MM cells. Importantly, silencing of KDM3A, KLF2 or IRF4 both decreases MM cell adhesion to bone marrow stromal cells and reduces MM cell homing to the bone marrow, in association with decreased ITGB7 expression in MAF-translocated MM cell lines. Our results indicate that the KDM3A–KLF2–IRF4 pathway plays an essential role in MM cell survival and homing to the bone marrow, and therefore represents a therapeutic target.

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Control of Histone H3 Lysine 9 (H3K9) Methylation State via Cooperative Two-step Demethylation by Jumonji Domain Containing 1A (JMJD1A) Homodimer

Cited by 29 publications

References 50 publications

Systematic characterization of chromatin modifying enzymes identifies KDM3B as a critical regulator in castration resistant prostate cancer

Systematic characterization of chromatin modifying enzymes identifies KDM3B as a critical regulator in castration resistant prostate cancer

Regulation of c-Myc expression by the histone demethylase JMJD1A is essential for prostate cancer cell growth and survival

The KDM3A–KLF2–IRF4 axis maintains myeloma cell survival

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