Histone methyltransferase SETDB1 regulates liver cancer cell growth through methylation of p53

Qi, Fei; Shang, Ke; Zhang, Jianhua; Chuai, Shannon; Kong, Desheng; Zhou, Tianlun; Fu, Shijun; Liang, Ying; Li, Chong; Chen, Zhi; Zhao, Yuan; Yu, Zhengtian; Huang, Zheng; Hu, Min; Ying, Haiyan; Chen, Zhui; Zhang, Yun; Feng, Xing; Zhu, Jidong; Xu, Haiyan; Zhao, Kehao; Lu, Chris X.; Atadja, Peter; Xiao, Zhi‐Xiong Jim; Li, En; Shou, Jianyong

doi:10.1038/ncomms9651

Cited by 135 publications

(138 citation statements)

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“…Besides the transcriptional regulatory function during oogenesis, we cannot exclude a post-transcriptional role of Setdb1 in meiosis by modifying proteins directly (Fei et al, 2015;Kaustov et al, 2011;Van Duyne et al, 2008). Identifying such Setdb1 targets in oocytes, however, is a challenging prospect.…”

Section: Discussionmentioning

confidence: 99%

The methyltransferase Setdb1 is essential for meiosis and mitosis in mouse oocytes and early embryos

et al. 2016

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Oocytes develop the competence for meiosis and early embryogenesis during their growth. Setdb1 is a histone H3 lysine 9 (H3K9) methyltransferase required for post-implantation development and has been implicated in the transcriptional silencing of genes and endogenous retroviral elements (ERVs). To address its role in oogenesis and pre-implantation development, we conditionally deleted Setdb1 in growing oocytes. Loss of Setdb1 expression greatly impaired meiosis. It delayed meiotic resumption, altered the dynamics of chromatin condensation, and impaired kinetochore-spindle interactions, bipolar spindle organization and chromosome segregation in more mature oocytes. The observed phenotypes related to changes in abundance of specific transcripts in mutant oocytes. Setdb1 maternally deficient embryos arrested during pre-implantation development and showed comparable defects during cell cycle progression and in chromosome segregation. Finally, transcriptional profiling data indicate that Setdb1 downregulates rather than silences expression of ERVK and ERVLMaLR retrotransposons and associated chimearic transcripts during oogenesis. Our results identify Setdb1 as a newly discovered meiotic and embryonic competence factor safeguarding genome integrity at the onset of life.

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Section: Discussionmentioning

confidence: 99%

The methyltransferase Setdb1 is essential for meiosis and mitosis in mouse oocytes and early embryos

et al. 2016

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“…The TP53 mutation at codon 249 (R249S) could induce the transcription of MLL and the association with the switch/sucrose non-fermentable nucleosome remodeling complex [20]. In addition, R249S mutation could induce the transcription of SET domain bifurcated 1 (SETDB1), which is known as a histone H3 lysine 9 (H3K9) methyltransferase; SETDB1 could also suppress the degradation of the R249S mutation and play a role in hepatocarcinogenesis [21]. The codon 249 is known as a mutational hotspot of the TP53 gene in aflatoxin B1 (AFB1)-induced hepatocarcinogenesis, which is a well-known carcinogen for HCC [22]; induction of the R249S mutation is also reportedly associated with exposure to AFB1 [23].…”

Section: Association Between Mutation Of Cancer-related Genes and Epimentioning

confidence: 99%

Clinical Significance of Epigenetic Alterations in Human Hepatocellular Carcinoma and Its Association with Genetic Mutations

Nishida

Kudo²

2016

Dig Dis

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Accumulation of genetic and epigenetic alterations is a hallmark of cancer genomes, including those in hepatocellular carcinoma (HCC). Particularly, in human HCC, epigenetic changes are more frequently observed than genetic changes in a variety of cancer-related genes, suggesting a potential role for epigenetic alterations during hepatocarcinogenesis. Several environmental factors, such as inflammation, obesity, and steatosis, are reported to affect the epigenetic status in hepatocytes, which could play a role in HCC development. In addition, genetic mutations in histone modulators and chromatin regulators would be critical for the acceleration of epigenetic alteration. It is also possible that major genetic mutations of HCC, such as TP53 and CNTTB1 mutations, are associated with the disturbance of epigenetic integrity. For example, specific TP53 mutations frequently induced by aflatoxin B1 exposure might affect histone modifiers and nucleosome remodelers. Generally, epigenetic alteration is reversible, because of which dysregulation of transcription takes place, without affecting protein structure. Therefore, differentiation therapy is one of the potential approaches for HCC with advanced epigenetic alterations. On the other hand, a tumor carrying an accumulation of genetic mutations would result in many abnormal proteins that could be recognized as non-self and could be targets for immune reactions; thus, immune-checkpoint blockers should be effective for HCCs with genetic hypermutation. Although the emergence of genetic and epigenetic alterations could be linked to each other and there could be some crossover or convergence between these cancer pathways, characterization of the mutation spectrum of genetic and epigenetic alterations could influence future HCC treatment.

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“…100 Increasing reports indicate a critical role for SETDB1 in liver carcinogenesis. 101,102 In liver cancer cells, p53 undergoes a gain of function mutation (R249S), and also show an overexpression of SETDB1. SETDB1 methylates p53 at lysine 370 and, thereby, stabilizes it to regulate cell growth.…”

mentioning

confidence: 99%

“…Attenuation of SETDB1 abrogates the methylation of mutant p53, resulting in a decrease in S phase cells and proliferation. 102 Paclitaxel, a chemotherapeutic drug, negatively regulates SETDB1 expression. The repressive action of paclitaxel on SETDB1 is mediated by p53-dependent recruitment of SUV39H1 at the SETDB1 promoter resulting in increased H3K9 repressive marks.…”

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A drive in SUVs: From development to disease

2017

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Progression of cells through distinct phases of the cell cycle, and transition into out-of-cycling states, such as terminal differentiation and senescence, is accompanied by specific patterns of gene expression. These cell fate decisions are mediated not only by distinct transcription factors, but also chromatin modifiers that establish heritable epigenetic patterns. Lysine methyltransferases (KMTs) that mediate methylation marks on histone and non-histone proteins are now recognized as important regulators of gene expression in cycling and non-cycling cells. Among these, the SUV39 sub-family of KMTs, which includes SUV39H1, SUV39H2, G9a, GLP, SETDB1, and SETDB2, play a prominent role. In this review, we discuss their biochemical properties, sub-cellular localization and function in cell cycle, differentiation programs, and cellular senescence. We also discuss their aberrant expression in cancers, which exhibit de-regulation of cell cycle and differentiation.

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Histone methyltransferase SETDB1 regulates liver cancer cell growth through methylation of p53

Cited by 135 publications

References 42 publications

The methyltransferase Setdb1 is essential for meiosis and mitosis in mouse oocytes and early embryos

The methyltransferase Setdb1 is essential for meiosis and mitosis in mouse oocytes and early embryos

Clinical Significance of Epigenetic Alterations in Human Hepatocellular Carcinoma and Its Association with Genetic Mutations

A drive in SUVs: From development to disease

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