Histone demethylase Kdm4b functions as a co-factor of C/EBPβ to promote mitotic clonal expansion during differentiation of 3T3-L1 preadipocytes

Guo, Liang; X, Li; Jx, Huang; Huang, Hongbiao; Yy, Zhang; Sw, Qian; Zhu, Hai‐Liang; Zhang, YD; Y, Liu; Kk, Wang; Qq, Tang

doi:10.1038/cdd.2012.75

Cited by 63 publications

(103 citation statements)

References 40 publications

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“…In MCE, C/EBP␤ and Kdm4b form a complex and transactivate cell cycle genes to promote the process of hyperplasia (10). When the cells exit MCE, C/EBP␤ is dually phosphorylated and occupies the promoter of C/EBP␣, leading to terminal differentiation of the cells.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have shown that phosphorylation of C/EBP␤ is essential in order for it to bind to the C/EBP␣ promoter (9). Studies from our laboratory have also shown that C/EBP␤ promotes MCE by controlling cell cycle gene expression (10). In order to explain how C/EBP␤ transactivates different genes during MCE and terminal adipocyte differentiation, we examined its potential cofactors using a yeast two-hybrid system (see Fig.…”

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confidence: 99%

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p300-Dependent Acetylation of Activating Transcription Factor 5 Enhances C/EBPβ Transactivation of C/EBPα during 3T3-L1 Differentiation

Zhao

Zhang

et al. 2014

Molecular and Cellular Biology

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bAdipogenesis is a multistep process by which 3T3-L1 preadipocytes differentiate into mature adipocytes through mitotic clonal expansion (MCE) and terminal differentiation. The CCAAT/enhancer-binding protein ␤ (C/EBP␤) is an important transcription factor that takes part in both of these processes. C/EBP␤ not only transactivates C/EBP␣ and the peroxisome proliferatoractivated receptor ␥ (PPAR␥), which cause 3T3-L1 preadipocytes to enter terminal adipocyte differentiation, but also is required to activate cell cycle genes necessary for MCE. The identification of potential cofactors of C/EBP␤ will help to explain how C/EBP␤ undertakes these specialized roles during the different stages of adipogenesis. In this study, we found that activating transcription factor 5 (ATF5) can bind to the promoter of C/EBP␣ via its direct interaction with C/EBP␤ (which is mediated via the p300-dependent acetylation of ATF5), leading to enhanced C/EBP␤ transactivation of C/EBP␣. We also show that p300 is important for the interaction of ATF5 with C/EBP␤ as well as for the binding activity of this complex on the C/EBP␣ promoter. Consistent with these findings, overexpression of ATF5 and an acetylated ATF5 mimic both promoted 3T3-L1 adipocyte differentiation, whereas short interfering RNA-mediated ATF5 downregulation inhibited this process. Furthermore, we show that the elevated expression of ATF5 is correlated with an obese phenotype in both mice and humans. In summary, we have identified ATF5 as a new cofactor of C/EBP␤ and examined how C/EBP␤ and ATF5 (acetylated by a p300-dependent mechanism) regulate the transcription of C/EBP␣.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

p300-Dependent Acetylation of Activating Transcription Factor 5 Enhances C/EBPβ Transactivation of C/EBPα during 3T3-L1 Differentiation

Zhao

Zhang

et al. 2014

Molecular and Cellular Biology

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“…These two factors serve as pleiotropic transactivators of many adipocyte-specific genes to promote and maintain the terminally differentiated phenotype. Besides its role in transactivation of PPAR␥ and C/EBP␣, C/EBP␤ is also involved in regulating mitotic clonal expansion, a cell proliferation process required for terminal adipocyte differentiation (9)(10)(11).…”

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confidence: 99%

Transactivation of Atg4b by C/EBPβ Promotes Autophagy To Facilitate Adipogenesis

Guo

Huang

Liu

et al. 2013

Molecular and Cellular Biology

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b Autophagy is a highly conserved self-digestion pathway involved in various physiological and pathophysiological processes. Recent studies have implicated a pivotal role of autophagy in adipocyte differentiation, but the molecular mechanism for its role and how it is regulated during this process are not clear. Here, we show that CCAAT/enhancer-binding protein ␤ (C/EBP␤), an important adipogenic factor, is required for the activation of autophagy during 3T3-L1 adipocyte differentiation. An autophagyrelated gene, Atg4b, is identified as a de novo target gene of C/EBP␤ and is shown to play an important role in 3T3-L1 adipocyte differentiation. Furthermore, autophagy is required for the degradation of Klf2 and Klf3, two negative regulators of adipocyte differentiation, which is mediated by the adaptor protein p62/SQSTM1. Importantly, the regulation of autophagy by C/EBP␤ and the role of autophagy in Klf2/3 degradation and in adipogenesis are further confirmed in mouse models. Our data describe a novel function of C/EBP␤ in regulating autophagy and reveal the mechanism of autophagy during adipocyte differentiation. These new insights into the molecular mechanism of adipose tissue development provide a functional pathway with therapeutic potential against obesity and its related metabolic disorders.

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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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Histone demethylase Kdm4b functions as a co-factor of C/EBPβ to promote mitotic clonal expansion during differentiation of 3T3-L1 preadipocytes

Cited by 63 publications

References 40 publications

p300-Dependent Acetylation of Activating Transcription Factor 5 Enhances C/EBPβ Transactivation of C/EBPα during 3T3-L1 Differentiation

p300-Dependent Acetylation of Activating Transcription Factor 5 Enhances C/EBPβ Transactivation of C/EBPα during 3T3-L1 Differentiation

Transactivation of Atg4b by C/EBPβ Promotes Autophagy To Facilitate Adipogenesis

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

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