KDM4A Coactivates E2F1 to Regulate the PDK-Dependent Metabolic Switch between Mitochondrial Oxidation and Glycolysis

Ly, Wang; Hung, Chiu Lien; Chen, Yun‐Ru; Yang, Joy C.; Wang, Junjian; Campbell, Mel; Izumiya, Yoshihiro; Chen, Hong Wu; Wang, Wen-Ching; Ann, David K.; Kung, Hsing Jien

doi:10.1016/j.celrep.2016.08.018

Cited by 75 publications

(63 citation statements)

References 43 publications

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“…S7E, treatment of HCT116 IDH-WT cells with this compound induced a dose-dependent increase in DSBs, which approached the amount seen in untreated HCT116 IDH-mutant cells. We observed this phenotype at doses ranging from 12.5–50 μM, which is within the reported range for the activity of this agent in cell culture studies (41, 42). NSC-636819 treatment in HCT116 IDH-mutant cells did not further increase comet tail moments, suggesting an epistatic interaction with the mutant IDH 1 gene.…”

Section: Resultssupporting

confidence: 87%

2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity

et al. 2017

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2-Hydroxyglutarate (2HG) exists as two enantiomers, (R)-2HG and (S)-2HG, and both are implicated in tumor progression via their inhibitory effects on α-ketoglutarate (αKG)-dependent dioxygenases. The former is an oncometabolite that is induced by the neomorphic activity conferred by isocitrate dehydrogenase-1 and -2 (IDH1/2) mutations, whereas the latter is produced under pathologic processes such as hypoxia. Here, we report that IDH1/2 mutations induce a homologous recombination (HR) defect that renders tumor cells exquisitely sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors. This “BRCAness” phenotype of IDH mutant cells can be completely reversed by treatment with small molecule inhibitors of the mutant IDH1 enzyme, and, conversely, it can be entirely recapitulated by treatment with either 2HG enantiomer alone in cells with intact IDH1/2 proteins. We demonstrate IDH1-dependent PARP inhibitor sensitivity in a range of clinically relevant models, including primary patient-derived glioma cells in culture and genetically matched tumor xenografts in vivo. These findings provide the basis for a possible therapeutic strategy exploiting the biological consequences of mutant IDH, rather than attempting to block 2HG production, by targeting the 2HG-dependent HR-deficiency with PARP inhibition. Furthermore, our results uncover an unexpected link between oncometabolites, altered DNA repair, and genetic instability.

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Section: Resultssupporting

confidence: 87%

2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity

et al. 2017

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“…Previous studies have reported that KDM4A upregulation has been observed in PC 9,27,28 . As KDM4A plays a key role in human cancer development, it is possible that in human cancers USP1 promotes the deubiquitination and stabilization of KDM4A.…”

Section: Resultsmentioning

confidence: 92%

RETRACTED: Targeting USP1‐dependent KDM4A protein stability as a potential prostate cancer therapy

et al. 2020

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Abbreviations: AR, androgen receptor; ARE, androgen-responsive element; DUB, deubiquitinating enzyme; H3K9, histone H3 on lysine 9; H3K36, histone H3 on lysine 36; HA-ub, HA-tagged ubiquitin; IB, immunoblot; IHC, immunohistochemistry; IP, immunoprecipitation; KDM4A, lysine-specific demethylase 4A; PC, prostate cancer; PTEN, phosphatase and tensin homolog; qPCR, quantitative PCR. AbstractThe histone demethylase lysine-specific demethylase 4A (KDM4A) is reported to be overexpressed and plays a vital in multiple cancers through controlling gene expression by epigenetic regulation of H3K9 or H3K36 methylation marks. However, the biological role and mechanism of KDM4A in prostate cancer (PC) remain unclear.Herein, we reported KDM4A expression was upregulation in phosphatase and tensin homolog knockout mouse prostate tissue. Depletion of KDM4A in PC cells inhibited their proliferation and survival in vivo and vitro. Further studies reveal that USP1 is a deubiquitinase that regulates KDM4A K48-linked deubiquitin and stability.Interestingly, we found c-Myc was a key downstream effector of the USP1-KDM4A/ androgen receptor axis in driving PC cell proliferation. Notably, upregulation of KDM4A expression with high USP1 expression was observed in most prostate tumors and inhibition of USP1 promotes PC cells response to therapeutic agent enzalutamide. Our studies propose USP1 could be an anticancer therapeutic target in PC.

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“…It is well known that JMJD2A can catalyse the demethylation of histone ninth/36th lysine (H3K9/K36) and regulate the expression of certain genes at the epigenetic level . Studies have shown that JMJD2A is highly expressed in a variety of tumours and is involved in the regulation of cancer cell proliferation, survival and conversion between glycolysis metabolism and mitochondrial oxidation . However, several researches show that histone H3 demethylase JMJD2A drives tumorigenesis and H3k9me3 was reduced in several cancers .…”

Section: Discussionmentioning

confidence: 99%

“…62 Studies have shown that JMJD2A is highly expressed in a variety of tumours [63][64][65] and is involved in the regulation of cancer cell proliferation, survival and conversion between glycolysis metabolism and mitochondrial oxidation. 66 However, several researches show that histone H3 demethylase JMJD2A drives tumorigenesis 65,[67][68][69][70][71] and H3k9me3 was reduced in several cancers. 72,73 In particular, regulating H3K9me3 activity contributes to cancer progression.…”

Section: Discussionmentioning

confidence: 99%

miR24‐2 accelerates progression of liver cancer cells by activating Pim1 through tri‐methylation of Histone H3 on the ninth lysine

Yang

Song

Meng

et al. 2020

J Cellular Molecular Medi

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Several microRNAs are associated with carcinogenesis and tumour progression. Herein, our observations suggest both miR24‐2 and Pim1 are up‐regulated in human liver cancers, and miR24‐2 accelerates growth of liver cancer cells in vitro and in vivo. Mechanistically, miR24‐2 increases the expression of N6‐adenosine‐methyltransferase METTL3 and thereafter promotes the expression of miR6079 via RNA methylation modification. Furthermore, miR6079 targets JMJD2A and then increased the tri‐methylation of histone H3 on the ninth lysine (H3K9me3). Therefore, miR24‐2 inhibits JMJD2A by increasing miR6079 and then increases H3K9me3. Strikingly, miR24‐2 increases the expression of Pim1 dependent on H3K9me3 and METTL3. Notably, our findings suggest that miR24‐2 alters several related genes (pHistone H3, SUZ12, SUV39H1, Nanog, MEKK4, pTyr) and accelerates progression of liver cancer cells through Pim1 activation. In particular, Pim1 is required for the oncogenic action of miR24‐2 in liver cancer. This study elucidates a novel mechanism for miR24‐2 in liver cancer and suggests that miR24‐2 may be used as novel therapeutic targets of liver cancer.

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KDM4A Coactivates E2F1 to Regulate the PDK-Dependent Metabolic Switch between Mitochondrial Oxidation and Glycolysis

Cited by 75 publications

References 43 publications

2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity

2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity

RETRACTED: Targeting USP1‐dependent KDM4A protein stability as a potential prostate cancer therapy

miR24‐2 accelerates progression of liver cancer cells by activating Pim1 through tri‐methylation of Histone H3 on the ninth lysine

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