Cancer-associated alteration of pericentromeric heterochromatin may contribute to chromosome instability
Roger B. Slee,Camie M. Steiner,Brittney-Shea Herbert,Gail H. Vance,Robert J. Hickey,Robert J. Hickey,T. Schwarz,T. Schwarz,S. Christan,S. Christan,Milan Radovich,Bryan P. Schneider,D. Schindelhauer,Brenda R. Grimes +13 more
TLDR
It is suggested that impaired maintenance of pericentromeric heterochromatin may contribute to CIN in cancer and be a novel therapeutic target.Abstract:
Many tumors exhibit elevated chromosome mis-segregation termed chromosome instability (CIN), which is likely to be a potent driver of tumor progression and drug resistance. Causes of CIN are poorly understood but probably include prior genome tetraploidization, centrosome amplification and mitotic checkpoint defects. This study identifies epigenetic alteration of the centromere as a potential contributor to the CIN phenotype. The centromere controls chromosome segregation and consists of higher-order repeat (HOR) alpha-satellite DNA packaged into two chromatin domains: the kinetochore, harboring the centromere-specific H3 variant centromere protein A (CENP-A), and the pericentromeric heterochromatin, considered important for cohesion. Perturbation of centromeric chromatin in model systems causes CIN. As cancer cells exhibit widespread chromatin changes, we hypothesized that pericentromeric chromatin structure could also be affected, contributing to CIN. Cytological and chromatin immunoprecipitation and PCR (ChIP–PCR)-based analyses of HT1080 cancer cells showed that only one of the two HORs on chromosomes 5 and 7 incorporate CENP-A, an organization conserved in all normal and cancer-derived cells examined. Contrastingly, the heterochromatin marker H3K9me3 (trimethylation of H3 lysine 9) mapped to all four HORs and ChIP–PCR showed an altered pattern of H3K9me3 in cancer cell lines and breast tumors, consistent with a reduction on the kinetochore-forming HORs. The JMJD2B demethylase is overexpressed in breast tumors with a CIN phenotype, and overexpression of exogenous JMJD2B in cultured breast epithelial cells caused loss of centromere-associated H3K9me3 and increased CIN. These findings suggest that impaired maintenance of pericentromeric heterochromatin may contribute to CIN in cancer and be a novel therapeutic target.read more
Citations
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Advances in Hypoxia-Inducible Factor Biology
Hani Choudhry,Adrian L. Harris +1 more
TL;DR: Understanding the complex networks underlying cellular and genomic regulation in response to hypoxia via HIF may identify novel and specific therapeutic targets.
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KDM4/JMJD2 Histone Demethylases: Epigenetic Regulators in Cancer Cells
William L. Berry,Ralf Janknecht +1 more
TL;DR: Multiple attempts are under way to develop KDM4 inhibitors, which could complement the existing arsenal of epigenetic drugs that are currently limited to DNA methyltransferases and histone deacetylases.
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Heterochromatin: Guardian of the Genome
TL;DR: It is proposed that more comprehensive analyses of heterochromatin roles in tumorigenesis will be integral to future innovations in cancer treatment and the importance of its maintenance for genome integrity is discussed.
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Catalog of Chromosome Aberrations in Cancer
TL;DR: The fifth edition of Mitelman's catalogue provides a staggering collection of karyotypes from more than 22 000 individual neoplasms, drawn from all over the world, and describes every karyotype according to the most recent terminology, namely the International System for Cytogenetic Nomenclature 1991.
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Human Centromeres Produce Chromosome-Specific and Array-Specific Alpha Satellite Transcripts that Are Complexed with CENP-A and CENP-C
TL;DR: It is shown that each human alpha satellite array produces a unique set of non-coding transcripts, and RNAs present at active centromeres are necessary for kinetochore assembly and cell-cycle progression.
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