The role of the histone demethylase KDM4A in cancer

Guerra-Calderas, Lissania; González‐Barrios, Rodrigo; Herrera, Luis A.; León, David Cantú de; Soto-Reyes, Ernesto

doi:10.1016/j.cancergen.2014.11.001

Cited by 74 publications

(74 citation statements)

References 104 publications

(103 reference statements)

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“…Gene ontology (GO) analysis identified nine significant pathways ( p <0.05) containing more than ten gene molecules (Fig 7C). Consistent with emerging evidence showing that JMJD2A is involved in various cancers [26], most of the pathways identified were cancer-related. To narrow down the genes for further validation, genes simultaneously present in more than five of the nine identified pathways were first selected (Fig 7D).…”

Section: Resultssupporting

confidence: 79%

“…In addition, virally induced JMJD2A SUMOylation appears to activate certain cellular oncogenic pathways, probably providing an explanation for the observation that viral lytic genes are always coexpressed with cellular cancer-associated pathways [46]. Indeed, accumulating studies have noted the overexpression of JMJD2A in various cancers (reviewed in [26]). JMJD2A overexpression may promote transformation by blocking oncogene-induced senescence through transcriptional repression of CHD5 [28].…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, we identified that KSHV lytic protein K-bZIP, a viral SUMO E3 ligase with specificity towards SUMO-2/3 [25], enhances SUMOylation of JMJD2A. Emerging evidence has underscored the association of JMJD2A activity with various cancers (reviewed in [26]). Interestingly, we found that wild-type (WT) but not SUMO-deficient mutant of JMJD2A was capable of rescuing the proliferation of JMJD2A knockdown cells.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

SUMO modification of a heterochromatin histone demethylase JMJD2A enables viral gene transactivation and viral replication

Yang¹,

Campbell

Chang

2017

PLoS Pathog

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Small ubiquitin-like modifier (SUMO) modification of chromatin has profound effects on transcription regulation. By using Kaposi’s sarcoma associated herpesvirus (KSHV) as a model, we recently demonstrated that epigenetic modification of viral chromatin by SUMO-2/3 is involved in regulating gene expression and viral reactivation. However, how this modification orchestrates transcription reprogramming through targeting histone modifying enzymes remains largely unknown. Here we show that JMJD2A, the first identified Jumonji C domain-containing histone demethylase, is the histone demethylase responsible for SUMO-2/3 enrichment on the KSHV genome during viral reactivation. Using in vitro and in vivo SUMOylation assays, we found that JMJD2A is SUMOylated on lysine 471 by KSHV K-bZIP, a viral SUMO-2/3-specific E3 ligase, in a SUMO-interacting motif (SIM)-dependent manner. SUMOylation is required for stabilizing chromatin association and gene transactivation by JMJD2A. These finding suggest that SUMO-2/3 modification plays an essential role in the epigenetic regulatory function of JMJD2A. Consistently, hierarchical clustering analysis of RNA-seq data showed that a SUMO-deficient mutant of JMJD2A was more closely related to JMJD2A knockdown than to wild-type. Our previous report demonstrated that JMJD2A coated and maintained the “ready to activate” status of the viral genome. Consistent with our previous report, a SUMO-deficient mutant of JMJD2A reduced viral gene expression and virion production. Importantly, JMJD2A has been implicated as an oncogene in various cancers by regulating proliferation. We therefore further analyzed the role of SUMO modification of JMJD2A in regulating cell proliferation. Interestingly, the SUMO-deficient mutant of JMJD2A failed to rescue the proliferation defect of JMJD2A knockdown cells. Emerging specific inhibitors of JMJD2A have been generated for evaluation in cancer studies. Our results revealed that SUMO conjugation mediates an epigenetic regulatory function of JMJD2A and suggests that inhibiting JMJD2A SUMOylation may be a novel avenue for anti-cancer therapy.

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Section: Resultssupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

SUMO modification of a heterochromatin histone demethylase JMJD2A enables viral gene transactivation and viral replication

Yang¹,

Campbell

Chang

2017

PLoS Pathog

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show abstract

“…Although KDM4A, 4B, and 4C are shown to be overexpressed in many human cancers and promote tumorigenesis through variety of mechanisms (1, 6, 27, 28), the mechanism by which KDM4B activates PLK1 transcription via BMYB in the late S-phase of PCa cells has not been reported before, thus we focused on this mechanism in this study. We found that KDM4B is the major isoform in PCa tumorigenesis compared to KDm4A and 4C.…”

Section: Discussionmentioning

confidence: 99%

KDM4/JMJD2 Histone Demethylase Inhibitors Block Prostate Tumor Growth by Suppressing the Expression of AR and BMYB-Regulated Genes

Duan

Rai

Roggero

et al. 2015

Chemistry & Biology

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Summary Histone lysine demethylase KDM4/JMJD2s are overexpressed in many human tumors including prostate cancer (PCa). KDM4s are co-activators of androgen receptor (AR) and thus potential therapeutic targets. Yet to date few KDM4 inhibitors that have anti-prostate tumor activity in vivo have been developed. Here we report the anti-tumor growth effect and molecular mechanisms of three novel KDM4 inhibitors (A1, I9, and B3). These inhibitors repressed the transcription of both AR and BMYB-regulated genes. Compound B3 is highly selective for a variety of cancer cell lines including PC3 cells that lack AR. B3 inhibited the in vivo growth of tumors derived from PC3 cells and ex vivo human PCa explants. We identified a novel mechanism by which KDM4B activates the transcription of polo-like kinase 1 (PLK1). B3 blocked the binding of KDM4B to the PLK1 promoter. Our studies suggested a potential mechanism-based therapeutic strategy for PCa and tumors with elevated KDM4B/PLK1 expression.

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“…Another report suggests that sumoylation of histone deacetylase 2 (HDAC2) interferes with DNA binding of p53 and alters expression of the p53 target (Wagner et al 2012). KDM4A is a nuclear protein (Salifou et al 2016) that is overexpressed in various cancer cells (Guerra-Calderas et al 2015). In addition, SUMO1 was expressed at much higher levels in colon cancer cell lines compared to normal cells (Cubeñas-Potts and Matunis 2013).…”

Section: Introductionmentioning

confidence: 99%

Sumoylation of the histone demethylase KDM4A is required for binding to tumor suppressor p53 in HCT116 colon cancer cell lines

Park

Jang

2018

Animal Cells and Systems

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The histone demethylase lysine-specific demethylase 4A (KDM4A/Jmjd2A) has diverse functions, including involvement in gene regulation and cell cycle, and plays an oncogenic role in cancer cells. The modulation of KDM4A through post-translational modifications remains unclear. Here, we show that small ubiquitin-like modifier (SUMO) 1-mediated modification of KDM4A was required for interaction with tumor suppressor p53. Our data revealed that KDM4A is mainly sumoylated at lysine residue 471. However, the SUMO modification resulted in little change in subcellular localization, demethylase activity, or protein stability of KMD4A. Intriguingly, coimmunoprecipitation data revealed that sumoylation-defective mutants of KDM4A had a lower binding ability with p53 compared to that of wild-type KDM4A, suggesting a positive role for sumoylation in the interaction between KDM4A and p53. Together, these data suggest that KDM4A is post-translationally modified by SUMO, and this sumoylation may be a novel regulatory switch for controlling the interplay between KDM4A and p53.ARTICLE HISTORY

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The role of the histone demethylase KDM4A in cancer

Cited by 74 publications

References 104 publications

SUMO modification of a heterochromatin histone demethylase JMJD2A enables viral gene transactivation and viral replication

SUMO modification of a heterochromatin histone demethylase JMJD2A enables viral gene transactivation and viral replication

KDM4/JMJD2 Histone Demethylase Inhibitors Block Prostate Tumor Growth by Suppressing the Expression of AR and BMYB-Regulated Genes

Sumoylation of the histone demethylase KDM4A is required for binding to tumor suppressor p53 in HCT116 colon cancer cell lines

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