title: Cancer-associated alteration of pericentromeric heterochromatin may contribute to chromosome instability.
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.
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University School of Medicine (IUSM), Indianapolis, IN 46202, USA.
authors.forename: R B
authors.initials: RB
authors.lastname: Slee
authors.forename: C M
authors.initials: CM
authors.lastname: Steiner
authors.forename: B-S
authors.initials: BS
authors.lastname: Herbert
authors.forename: G H
authors.initials: GH
authors.lastname: Vance
authors.forename: R J
authors.initials: RJ
authors.lastname: Hickey
authors.forename: T
authors.initials: T
authors.lastname: Schwarz
authors.forename: S
authors.initials: S
authors.lastname: Christan
authors.forename: M
authors.initials: M
authors.lastname: Radovich
authors.forename: B P
authors.initials: BP
authors.lastname: Schneider
authors.forename: D
authors.initials: D
authors.lastname: Schindelhauer
authors.forename: B R
authors.initials: BR
authors.lastname: Grimes
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002503:Centromere / Q000235:genetics* / Q000378:metabolism*; D043171:Chromosomal Instability; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics; D005260:Female; D006570:Heterochromatin / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism; D018386:Kinetochores / Q000378:metabolism; D009361:Neoplasm Invasiveness
chemical_list: D006570:Heterochromatin; D006657:Histones; D056484:Jumonji Domain-Containing Histone Demethylases; C523637:KDM4B protein, human; C494424:KDM4A protein, human