Cancer-predisposition gene KLLN maintains pericentric H3K9 trimethylation protecting genomic stability

被引:15
作者
Nizialek, Emily A. [1 ,2 ,3 ]
Sankunny, Madhav [1 ,2 ]
Niazi, Farshad [1 ,2 ]
Eng, Charis [1 ,2 ,3 ,4 ,5 ]
机构
[1] Cleveland Clin, Genom Med Inst, Cleveland, OH 44195 USA
[2] Cleveland Clin, Lerner Res Inst, Cleveland, OH 44195 USA
[3] Case Western Reserve Univ, Dept Genet & Genome Sci, Cleveland, OH 44106 USA
[4] Cleveland Clin, Taussig Canc Inst, Cleveland, OH 44195 USA
[5] Case Western Reserve Univ, Germline High Risk Focus Grp, CASE Comprehens Canc Ctr, Cleveland, OH 44106 USA
关键词
EPIGENETIC REGULATION; TUMOR-SUPPRESSOR; NUCLEAR PTEN; HETEROCHROMATIN; TRANSCRIPTION; METHYLATION; GERMLINE; KILLIN; APOPTOSIS; SUV39H1;
D O I
10.1093/nar/gkv1481
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Maintenance of proper chromatin states and genomic stability is vital for normal development and health across a range of organisms. Here, we report on the role of KLLN in maintenance of pericentric H3K9 trimethylation (H3K9me3) and genomic stability. Germline hypermethylation of KLLN, a gene uncovered well after the human genome project, has been linked to Cowden cancer-predisposition syndrome (CS) in PTEN wild-type cases. KLLN first identified as a p53-dependent tumor suppressor gene, was believed to bind randomly to DNA and cause S-phase arrest. Using chromatin immunoprecipitation-based sequencing (ChIP-seq), we demonstrated that KLLN binds to DNA regions enriched with H3K9me3. KLLN overexpression correlated with increased H3K9 methyltransferase activity and increased global H3K9me3, while knockdown of KLLN had an opposite effect. We also found KLLN to localize to pericentric regions, with loss of KLLN resulting in dysregulation of pericentric heterochromatin, with consequent chromosomal instability manifested by increased micronuclei formation and numerical chromosomal aberrations. Interestingly, we show that KLLN interacts with DBC1, with consequent abrogation of DBC1 inhibition of SUV39H1, a H3K9 methyltransferase, suggesting the mode of KLLN regulating H3K9me3. These results suggest a critical role for KLLN as a potential regulator of pericentric heterochromatin formation, genomic stability and gene expression.
引用
收藏
页码:3586 / 3594
页数:9
相关论文
共 25 条
[1]   Germline and Somatic DNA Methylation and Epigenetic Regulation of KILLIN in Renal Cell Carcinoma [J].
Bennett, Kristi L. ;
Campbell, Rebecca ;
Ganapathi, Shireen ;
Zhou, Ming ;
Rini, Brian ;
Ganapathi, Ram ;
Neumann, Hartmut P. H. ;
Eng, Charis .
GENES CHROMOSOMES & CANCER, 2011, 50 (08) :654-661
[2]   Germline Epigenetic Regulation of KILLIN in Cowden and Cowden-like Syndrome [J].
Bennett, Kristi L. ;
Mester, Jessica ;
Eng, Charis .
JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 2010, 304 (24) :2724-2731
[3]   PTEN Interacts with Histone H1 and Controls Chromatin Condensation [J].
Chen, Zhu Hong ;
Zhu, Minglu ;
Yang, Jingyi ;
Liang, Hui ;
He, Jinxue ;
He, Shiming ;
Wang, Pan ;
Kang, Xi ;
McNutt, Michael A. ;
Yin, Yuxin ;
Shen, Wen H. .
CELL REPORTS, 2014, 8 (06) :2003-2014
[4]   HDAC3 Is Negatively Regulated by the Nuclear Protein DBC1 [J].
Chini, Claudia C. S. ;
Escande, Carlos ;
Nin, Veronica ;
Chini, Eduardo N. .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2010, 285 (52) :40830-40837
[5]   Killin is a p53-regulated nuclear inhibitor of DNA synthesis [J].
Cho, Yong-jig ;
Liang, Peng .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2008, 105 (14) :5396-5401
[6]   Will the real Cowden syndrome please stand up: revised diagnostic criteria [J].
Eng, C .
JOURNAL OF MEDICAL GENETICS, 2000, 37 (11) :828-830
[7]   Mapping and analysis of chromatin state dynamics in nine human cell types [J].
Ernst, Jason ;
Kheradpour, Pouya ;
Mikkelsen, Tarjei S. ;
Shoresh, Noam ;
Ward, Lucas D. ;
Epstein, Charles B. ;
Zhang, Xiaolan ;
Wang, Li ;
Issner, Robbyn ;
Coyne, Michael ;
Ku, Manching ;
Durham, Timothy ;
Kellis, Manolis ;
Bernstein, Bradley E. .
NATURE, 2011, 473 (7345) :43-U52
[8]   Deleted in Breast Cancer 1, a Novel Androgen Receptor (AR) Coactivator That Promotes AR DNA-binding Activity [J].
Fu, Junjiang ;
Jiang, Jun ;
Li, Jiwen ;
Wang, Shanshan ;
Shi, Guang ;
Feng, Qin ;
White, Eileen ;
Qin, Jun ;
Wong, Jiemin .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2009, 284 (11) :6832-6840
[9]   Nuclear PTEN tumor-suppressor functions through maintaining heterochromatin structure [J].
Gong, Lili ;
Govan, Jeane M. ;
Evans, Elizabeth B. ;
Dai, Hui ;
Wang, Edward ;
Lee, Szu-Wei ;
Lin, Hui-Kuan ;
Lazar, Alexander J. ;
Mills, Gordon B. ;
Lin, Shiaw-Yih .
CELL CYCLE, 2015, 14 (14) :2323-2332
[10]   Hallmarks of Cancer: The Next Generation [J].
Hanahan, Douglas ;
Weinberg, Robert A. .
CELL, 2011, 144 (05) :646-674