ZMYND10 downregulates cyclins B1 and D1 to arrest cell cycle by trimethylating lysine 9 on histone 3  

作　　者：Long-Ji Wu Xiang-Ning Zhang Jian Wang Xia Kong Bi-Ying Zheng Jing Huang Hong-Bing Yu Zhi-Wei He 

机构地区：[1]Department of Pathophysiology,School of Basic Medical Science,Guangdong Medical University,Dongguan,Guangdong,China [2]Chinese-American Tumor Institute,Guangdong Provincial Key Laboratory of Medical Diagnostics,Guangdong,China. [3]Department of Clinical Microbiology,Institute of Laboratory Medicine,Guangdong Medical University,Dongguan,Guangdong,China.

出　　处：《Life Research》2021年第4期17-24,共8页TMR生命研究

基　　金：Guangdong Medical Scientific Research Foundation,Guangdong Provincial Health Commission,China(2018A256 to XZ);from Guangdong Provincial Natural Scientific Foundation(2018A03030739 to JW and XZ);the Key Fostering Program of the Scientific Foundation of Guangdong Medical University,China(2019006 to JW).

摘　　要：The BLU gene coding for zinc finger,MYND-type containing 10(ZMYND10)protein is mapped on chromosomal region 3p21.It is frequently lost in some kinds of cancers due to hypermethylation on its promoter region and identified as a tumour suppressor gene.The underlying mechanisms for BLU-mediated tumor suppression remain unclear.BLU has been reported to disturb cell cycle progression.The present study aims at examining whether ZMYND10 prevents progression of the cell cycle by targeting to repressive histone marks and downregulating the level of cyclins.Proteins structurally similar with ZMYND10 have been shown to recognize DNA sequence upstream of coding portion of the gene encoding cell cycle regulators.Enzymes,notably demethylases modifying the lysine residues are over-expressed line oncoproteins,and targeted in anti-cancer therapy.BLU was re-expressed in H1299 and HepG2 cells.The level of cyclin D1,cyclin B1 and trimethylate lysine 9 on histone 3(H3K9me3)and the binding of BLU with SIN3A(a component of the co-repressor)were detected.Cell cycle profile was measured.The evolutionary relationship between ZMYND10 and other ZMYND proteins was analysed by phylogenetic tree construction.We found that BLU expression induced G1 arrest in H1299 cells,and induced G1/G2 arrest in HepG2 cells.Cell cycle arrest was correlated with reduced activities and levels of cyclins;cyclin D1 was downregulated in H1299 cells;Both cyclin B1 and D1 were downregulated in HepG2 cells;and that BLU was associated with SIN3A.In both cell lines,the expression of H3K9me3 was induced.BLU was clustered with histone methyltransferase SMYD3 and SMYD1 on the same clade of the deduced phylogenetic tree.The results thus suggested that ZMYND10 encoded by BLU inhibited cyclins activity to prevent cell cycle progression through interaction with repressors and histone repressive marks to block the expression of genes coding for cyclins.

关 键 词：BLU/ZMYND10 tumor suppression cell cycle arrest CYCLIN trimethylated lysine 9 on histone 3 

分 类 号：R73[医药卫生—肿瘤]