Acetylation of MAT IIα represses tumour cell growth and is decreased in human hepatocellular cancer

Yang, Hong-Chang; Xu, Yingying; Zhao, Xiangmo; Zou, Shaowu; Zhang, Ye; Zhang, Min; Li, Jintao; Ren, Feng; Wang, Liying; Lei, Qun-Ying

doi:10.1038/ncomms7973

Cited by 52 publications

(65 citation statements)

References 26 publications

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“…Acetylation modification of metabolic enzymes is very dynamic in response to different physiological signals, such as alteration of glucose, amino acids and other metabolites. 33,34,47,48 The present study demonstrates that E1 promotes HSD17B4 acetylation via promoting the interaction between CREBBP and HSD17B4 and decreases its stability as well. CREBBP and SIRT3 control the K669 acetylation level of HSD17B4 in response to E1, and subsequently regulate its degradation (Fig.…”

Section: Discussionsupporting

confidence: 53%

Acetylation targets HSD17B4 for degradation via the CMA pathway in response to estrone

Zhang

Yao

et al. 2017

Autophagy

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Dysregulation of hormone metabolism is implicated in human breast cancer. 17b-hydroxysteroid dehydrogenase type 4 (HSD17B4) catalyzes the conversion of estradiol (E2) to estrone (E1), and is associated with the pathogenesis and development of various cancers. Here we show that E1 upregulates HSD17B4 acetylation at lysine 669 (K669) and thereby promotes HSD17B4 degradation via chaperonemediated autophagy (CMA), while a single mutation at K669 reverses the degradation and confers migratory and invasive properties to MCF7 cells upon E1 treatment. CREBBP and SIRT3 dynamically control K669 acetylation level of HSD17B4 in response to E1. More importantly, K669 acetylation is inversely correlated with HSD17B4 in human breast cancer tissues. Our study reveals a crosstalk between acetylation and CMA degradation in HSD17B4 regulation, and a critical role of the regulation in the malignant progression of breast cancer.

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Section: Discussionsupporting

confidence: 53%

Acetylation targets HSD17B4 for degradation via the CMA pathway in response to estrone

Zhang

Yao

et al. 2017

Autophagy

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“…1). While the expression of MAT1A (Cai et al 1996) is downregulated the levels of both, MAT2A (Cai et al 1996;Liu et al 2011;Tomasi et al 2015;Yang et al 2015) and MAT2B (Martínez-Chantar et al 2003a), gene products are increased. This relates with isozyme switch of MAT I/III to MAT II that leads to lowering of SAM concentration Frau et al 2013) with subsequent dysregulation in methylation of DNA (Frau et al 2012;Tomasi et al 2012) and histones with impact on the gene expression (Mentch et al 2015).…”

Section: Effect Of Altered Expression Of Mat Genes On Carcinogenesismentioning

confidence: 99%

“…Since, α2 subunit of MAT II in addition to its enzymatic role in process of SAM synthesis possesses also several signaling functions. Increased acetylation (Yang et al 2015) or suppressed sumoylation (Tomasi et al 2015) of α2 subunit exerts anti-proliferative effect on cancer cells. While an acetylation of α2 subunit promotes its ubiquitination and subsequent proteasomal degradation and represses the tumor growth (Yang et al 2015), sumoylation of α2 subunit is linked with its increased stability and enhanced expression of Bcl-2 protein leading to cancer cell survival and growth (Tomasi et al 2015).…”

Section: Effect Of Altered Expression Of Mat Genes On Carcinogenesismentioning

confidence: 99%

“…Increased acetylation (Yang et al 2015) or suppressed sumoylation (Tomasi et al 2015) of α2 subunit exerts anti-proliferative effect on cancer cells. While an acetylation of α2 subunit promotes its ubiquitination and subsequent proteasomal degradation and represses the tumor growth (Yang et al 2015), sumoylation of α2 subunit is linked with its increased stability and enhanced expression of Bcl-2 protein leading to cancer cell survival and growth (Tomasi et al 2015). The regulatory role of MAT α2 subunit on the expression could be mediated by its interaction with several transcription factors and capability to function as a transcriptional co-repressor (Katoh et al 2011;Kera et al 2013;Tomasi et al 2015).…”

Section: Effect Of Altered Expression Of Mat Genes On Carcinogenesismentioning

confidence: 99%

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Role of S-adenosylmethionine cycle in carcinogenesis

Murín¹,

Vidomanová²,

Kowtharapu³

et al. 2017

gpb

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Abstract. Alterations in enzymatic activities underlying the cellular capacity to maintain functional S-adenosylmethionine (SAM) cycle are associated with modified levels of its constituents. Since SAM is the most prominent donor of methyl group for sustaining the methylation pattern of macromolecules by methyltransferases, its availability is an essential prerequisite for sustaining the methylation pattern of nucleic acids and proteins. In addition, increased intracellular concentrations of S-adenosylhomocysteine and homocysteine, another two constituents of SAM cycle, exerts an inhibitory effect on the enzymatic activity of methyltranferases. While methylation pattern of DNA and histones is considered as an important regulatory hallmark in epigenetically regulated gene expression, amended methylation of several cellular proteins, including transcription factors, affects their activity and stability. Indeed, varied DNA methylome is a common consequence of disturbed SAM cycle and is linked with molecular changes underlying the transformation of the cells that may underlay the carcinogenesis. Here we summarize the recent evidences about the impact of disturbed SAM cycle on carcinogenesis.

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“…Another possibility can be the gene-specific recruitment of DNA demethylases (see following section α-KG AND DNA DEMETHYLATION). Other studies also suggested the local recruitment of SAM synthase (19,25,26,51). For instance, a multi-protein complex SAM-integrating transcription repression (SAMIT) was proposed that includes MATs to produce SAM locally to repress gene expression through DNA methylation (25,26).…”

Section: S-adenosyl-methionine and Methylationmentioning

confidence: 99%

Compartmentation of Metabolites in Regulating Epigenomes of Cancer

Zhao¹,

Wang

Di³

2016

Mol Med

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Covalent modifications of DNA and histones are important epigenetic events and the genomewide reshaping of epigenetic markers is common in cancer. Epigenetic markers are produced by enzymatic reactions, and some of these reactions require the presence of metabolites, specifically Epigenetic Enzyme Required Metabolites (EERMs), as cofactors. Recent studies found that the abundance of these EERMs correlates with epigenetic enzyme activities. Also, the subcellular compartmentation, especially the nuclear localization of these EERMs, may play a role in regulating the activities of epigenetic enzymes. Moreover, genespecific recruitment of enzymes that produce the EERMs in the proximity of the epigenetic modification events accompanying the regulation of gene expression, were proposed. Therefore, it is important to summarize findings of EERMs in regulating epigenetic modifications at both the DNA and histone levels, and to understand how EERMs contribute to cancer development by addressing their global versus local distribution.

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Acetylation of MAT IIα represses tumour cell growth and is decreased in human hepatocellular cancer

Cited by 52 publications

References 26 publications

Acetylation targets HSD17B4 for degradation via the CMA pathway in response to estrone

Acetylation targets HSD17B4 for degradation via the CMA pathway in response to estrone

Role of S-adenosylmethionine cycle in carcinogenesis

Compartmentation of Metabolites in Regulating Epigenomes of Cancer

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