The histone demethylase JMJD2A/KDM4A links ribosomal RNA transcription to nutrients and growth factors availability

Salifou, Kader; Ray, Sujoy; Verrier, Laure; Aguirrebengoa, Marion; Trouche, Didier; Panov, Kostya I.; Vandromme, Marie

doi:10.1038/ncomms10174

Cited by 36 publications

(37 citation statements)

References 45 publications

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“…Another human protein involved in H3K36me2/3 removal is KDM4A [69]. This enzyme, which also removes H3K9me3, is highly amplified in human tumors [70] and is localized in the nucleolus where it regulates rDNA transcription [71]. Future studies will be needed to determine which functions of KDM4A are specifically mediated through its action on H3K36.…”

Section: Regulation Of Set2 and H3k36 Methylationmentioning

confidence: 99%

Shaping the cellular landscape with Set2/SETD2 methylation

McDaniel

Strahl

2017

Cell. Mol. Life Sci.

115

108

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Chromatin structure is a major barrier to gene transcription that must be disrupted and re-set during each round of transcription. Central to this process is the Set2/SETD2 methyltransferase that mediates co-transcriptional methylation to histone H3 at lysine 36 (H3K36me). Studies reveal that H3K36me not only prevents inappropriate transcriptional initiation from arising within gene bodies, but that it has other conserved functions that include the repair of damaged DNA and regulation of pre-mRNA splicing. Consistent with the importance of Set2/SETD2 in chromatin biology, mutations of SETD2, or mutations at or near H3K36 in H3.3, have recently been found to underlie cancer development. This review will summarize the latest insights into the functions of Set2/SETD2 in genome regulation and cancer development.

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Section: Regulation Of Set2 and H3k36 Methylationmentioning

confidence: 99%

Shaping the cellular landscape with Set2/SETD2 methylation

McDaniel

Strahl

2017

Cell. Mol. Life Sci.

115

108

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“…For example, SGK1 has been recently shown to regulate RANBP1 gene transcription in colon carcinoma cells, thus affecting mitotic spindle function as well as cell sensitivity to taxanes (Amato et al, 2013). Furthermore, a more recent study has proposed that SGK1 mediates an increase in rRNA synthesis under conditions of PI3K activation by regulating the nucleolar localization of the histone demethylase KDM4A (Salifou et al, 2016). …”

Section: Sgk1 and Cancermentioning

confidence: 99%

Sgk1

Cristofano

2017

Current Topics in Developmental Biology

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Activation of the PI3K pathway is central to a variety of physiological and pathological processes. In these contexts, AKT is classically considered the de facto mediator of PI3K-dependent signaling. However, in recent years, accumulating data point to the existence of additional effectors of PI3K activity, parallel to and independent of AKT, that play critical and unique roles in mediating different developmental, homeostatic, and pathological processes. In this review, I summarize and discuss our current understanding of the function of the serine/threonine kinase SGK1 as a downstream effector of PI3K, and try to separate targets and pathways validated as uniquely SGK1-dependent from those shared with AKT.

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“…Aside from the TRAIL pathway silenced by KDM4A but not KDM4B, KDM4A and KDM4B likely regulate both overlapping and distinct gene targets 49 (e.g., cell cycle genes by both KDM4A and KDM4B; 37,50 c-Myc and ribosomal RNA genes by KDM4A and KDM4B; 51,52 B-Myb targets such as PLK1 by KDM4B 43 ). It is well known that cancer cells are addicted to the high levels of those genes for their uncontrolled growth and survival.…”

Section: Discussionmentioning

confidence: 99%

Silencing the epigenetic silencer KDM4A for TRAIL and DR5 simultaneous induction and antitumor therapy

Wang

et al. 2016

Cell Death Differ

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Recombinant TRAIL and agonistic antibodies to death receptors (DRs) have been in clinical trial but displayed limited anti-cancer efficacy. Lack of functional DR expression in tumors is a major limiting factor. We report here that chromatin regulator KDM4A/ JMJD2A, not KDM4B, has a pivotal role in silencing tumor cell expression of both TRAIL and its receptor DR5. In TRAIL-sensitive and -resistant cancer cells of lung, breast and prostate, KDM4A small-molecule inhibitor compound-4 (C-4) or gene silencing strongly induces TRAIL and DR5 expression, and causes TRAIL-dependent apoptotic cell death. KDM4A inhibition also strongly sensitizes cells to TRAIL. C-4 alone potently inhibits tumor growth with marked induction of TRAIL and DR5 expression in the treated tumors and effectively sensitizes them to the newly developed TRAIL-inducer ONC201. Mechanistically, C-4 does not appear to act through the Akt-ERK-FOXO3a pathway. Instead, it switches histone modifying enzyme complexes at promoters of TRAIL and DR5 transcriptional activator CHOP gene by dissociating KDM4A and nuclear receptor corepressor (NCoR)-HDAC complex and inducing the recruitment of histone acetylase CBP. Thus, our results reveal KDM4A as a key epigenetic silencer of TRAIL and DR5 in tumors and establish inhibitors of KDM4A as a novel strategy for effectively sensitizing tumors to TRAIL pathway-based therapeutics. 1-5 The binding triggers configurational changes in the receptor trimer and leads to formation of the deathinducing signaling complex (DISC). Depending on cellular context, extrinsic and/or intrinsic pathway of apoptosis is induced with an initial activation of caspase-8 and -10 at DISC and a subsequent activation of the effector caspases such as caspase -3 or -7. The high-tumor cell selectivity and potency in induction of cell death by TRAIL pathway prompted development of therapeutics in the forms of recombinant soluble TRAIL and agonistic TRAIL-R antibodies. 6,7 However, recent clinical trials demonstrated very limited therapeutic benefits. 8,9 Major resistance mechanisms include low expression and/or function of the TRAIL receptors, overexpression of TRAIL decoy receptors (DcRs) and aberrant expression/activation of the anti-apoptotic proteins, such as c-Flip, Bcl-2 family members and IAPs.10,11 Many synthetic or natural agents and cellular pathways have been identified in sensitizing cancer cells to TRAIL.12,13 Given the limited stability and/or bio-distribution of the current TRAIL-based therapies, alternative strategies are being sought to induce tumor cell-endogenous TRAIL expression to block tumor growth. For example, a cell-based screening for TRAIL gene promoter activator identified small-molecule ONC210/TIC10. The subsequent encouraging results of ONC201 from xenograft tumor studies led to its recent entry into clinical efficacy evaluation. 14,15 ONC201 apparently induces TRAIL in cancer cells through inhibition of Akt and ERK kinase signaling and promoting nuclear translocation of Foxo3a. Interestingly, it can also upregulate DR5. ...

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The histone demethylase JMJD2A/KDM4A links ribosomal RNA transcription to nutrients and growth factors availability

Cited by 36 publications

References 45 publications

Shaping the cellular landscape with Set2/SETD2 methylation

Shaping the cellular landscape with Set2/SETD2 methylation

Sgk1

Silencing the epigenetic silencer KDM4A for TRAIL and DR5 simultaneous induction and antitumor therapy

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