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Cancer-Associated Alteration of Pericentromeric Heterochromatin May Contribute to Chromosome Instability

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Cancer-Associated Alteration of Pericentromeric Heterochromatin May Contribute to Chromosome Instability Oncogene (2012) 31, 3244–3253 & 2012 Macmillan Publishers Limited All rights reserved 0950-9232/12 www.nature.com/onc ORIGINAL ARTICLE Cancer-associated alteration of pericentromeric heterochromatin may contribute to chromosome instability RB Slee1,2, CM Steiner1, B-S Herbert1,2, GH Vance1,2, RJ Hickey2,3,5, T Schwarz4,6, S Christan4,7, M Radovich1, BP Schneider1,2,3, D Schindelhauer4,8 and BR Grimes1,2 1Department of Medical and Molecular Genetics, Indiana University School of Medicine (IUSM), Indianapolis, IN, USA; 2Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, USA; 3Department of Medicine, IUSM, Indianapolis, IN, USA and 4Department of Medical Genetics, Ludwig Maximilians University, Munich, Germany Many tumors exhibit elevated chromosome mis-segrega- Oncogene (2012) 31, 3244–3253; doi:10.1038/onc.2011.502; tion termed chromosome instability (CIN), which is likely published online 28 November 2011 to be a potent driver of tumor progression and drug resistance. Causes of CIN are poorly understood but Keywords: pericentromeric heterochromatin; chromo- probably include prior genome tetraploidization, centro- some instability; JMJD2 demethylase some 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 Introduction of higher-order repeat (HOR) alpha-satellite DNA packaged into two chromatin domains: the kinetochore, Cancer cells accumulate somatic mutations and other harboring the centromere-specific H3 variant centromere genomic rearrangements, which impair the normal protein A (CENP-A), and the pericentromeric hetero- mechanisms controlling cell proliferation and differen- chromatin, considered important for cohesion. Perturba- tiation, culminating in malignancy. One mechanism to tion of centromeric chromatin in model systems causes accelerate the loss or gain of tumor suppressor genes CIN. As cancer cells exhibit widespread chromatin and oncogenes, which often accompanies tumorigenesis, changes, we hypothesized that pericentromeric chromatin is chromosome mis-segregation resulting in the gain or structure could also be affected, contributing to CIN. loss of entire chromosomes (aneuploidy). The majority Cytological and chromatin immunoprecipitation and PCR of solid tumors exhibit numerical chromosomal (ChIP–PCR)-based analyses of HT1080 cancer cells abnormality (Mitelman et al., 1994). Although clonal showed that only one of the two HORs on chromosomes selection of rare aneuploid cells arising from basal 5 and 7 incorporate CENP-A, an organization conserved mis-segregation rates may partly account for tumor in all normal and cancer-derived cells examined. Con- aneuploidy (Cahill et al., 1999), many tumors are trastingly, the heterochromatin marker H3K9me3 (tri- thought to acquire an elevated mis-segregation rate methylation of H3 lysine 9) mapped to all four HORs and referred to as chromosomal instability (CIN), which has ChIP–PCR showed an altered pattern of H3K9me3 been proposed as a potent driver of tumor progression in cancer cell lines and breast tumors, consistent with and drug resistance (Kops et al., 2005). Likely causes of a reduction on the kinetochore-forming HORs. The CIN include multipolar mitoses following genome JMJD2B demethylase is overexpressed in breast tumors tetraploidization and centrosome amplification, chro- with a CIN phenotype, and overexpression of exogenous matid cohesion defects and impairment of the mitotic JMJD2B in cultured breast epithelial cells caused loss checkpoint pathways that ensure faithful chromosome of centromere-associated H3K9me3 and increased CIN. segregation (Thompson et al., 2010). However, the full These findings suggest that impaired maintenance of spectrum of changes underlying the CIN phenotype pericentromeric heterochromatin may contribute to CIN remains to be uncovered. This study presents new in cancer and be a novel therapeutic target. evidence implicating epigenetic impairment of the centromere as a contributing factor. Correspondence: Dr BR Grimes, Department of Medical and The centromere is the nucleoprotein complex at the Molecular Genetics, Indiana University School of Medicine, Indiana- core of the segregation machinery. Its functions include polis, IN 46202, USA. E-mail: [email protected] sister chromatid cohesion, attachment to the mitotic 5Current address: City of Hope, Duarte, CA, USA. spindle and management of the mitotic checkpoint. 6Current address: University of Wurzburg, Germany. Centromeres assemble on the megabase-sized blocks 7Current address: Technical University of Munich, Germany. of alpha-satellite DNA located at the primary constric- 8Current address: Chromosome Medicine Procurement, Therese- tion of all human chromosomes. Alpha-satellite DNA Studer-Str. 47, 80797 Munich, Germany. Received 15 August 2011; revised 25 September 2011; accepted 26 comprises tandem 171 bp monomers. Groups of mono- September 2011; published online 28 November 2011 mers are themselves reiterated, giving rise to a higher-order Pericentromeric heterochromatin changes in cancer RB Slee et al 3245 repeat (HOR) structure, which is unique to each required for proper chromosome segregation in mice centromere (Warburton and Willard, 1996). Despite (Peters et al., 2001), and the recently discovered JMJD2 this sequence heterogeneity, the basic chromatin archi- family of histone demethylases, which reverse trimethy- tecture of the centromere is well conserved and critical lation on H3K9 and K36 and have been implicated to its function (Verdaasdonk and Bloom, 2011). At the in tumorigenesis (Pedersen and Helin, 2010). JMJD2 microtubule attachment region (kinetochore) the core proteins antagonize formation of pericentromeric histone protein H3 is partially substituted by a H3K9me3 in mouse cells (Fodor et al., 2006), whereas centromere-specific H3 variant, centromere protein A overexpression of JMJD2B or JMJD2C has been (CENP-A) (Palmer et al., 1987; Sullivan and Karpen, reported in a range of cancers including breast cancer 2004). Alpha-satellite DNA flanking the kinetochore (Liu et al., 2009; Pedersen and Helin, 2010; Yang et al., assembles the pericentromeric heterochromatin com- 2010). Here, we find that overexpression of exogenous partment, which folds between sister kinetochores on JMJD2B in human breast epithelial cells can drive loss the metaphase chromosome, and is characterized by of centromere-associated H3K9me3 and increased CIN. abundant methylation of H3 at lysine 9 (H3K9) The possibility that disruption of pericentromeric (Sullivan and Karpen, 2004; Alonso et al., 2010). heterochromatin promotes CIN and cancer progression, CENP-A deposition provides a foundation for the by impairing centromere function, opens new research kinetochore (Vafa and Sullivan, 1997; Warburton avenues that may lead to therapeutic interventions et al., 1997), whereas methylated H3K9 serves as a targeting the affected pathways. docking site for the heterochromatin protein HP1 (Bannister et al., 2001), and has been implicated in centromeric cohesion at mitosis (Bernard et al., 2001; Results Guenatri et al., 2004; Alonso et al., 2010). The function of the centromere is therefore vulnerable to disruption Mapping the centromere 5 kinetochore in normal and of the pathways that maintain this unique chromatin cancer cells architecture. CENP-A overexpression is seen in breast A generic scheme of centromere organization showing and colon cancer and has been linked to a CIN assembly of CENP-A at the kinetochore and hetero- phenotype (Perou et al., 2000; Tomonaga et al., 2003; chromatin on flanking HOR alpha-satellite is shown in Amato et al., 2009), and engineered disruption of Figure 1a. To investigate how this scheme applies to an pericentromeric heterochromatin is associated with individual autosome, we examined the centromere of chromosome mis-segregation and tumorigenesis (Ekwall chromosome 5, which harbors two HORs, D5Z1 and et al., 1997; Bernard et al., 2001; Peters et al., 2001; D5Z2 (Finelli et al., 1996). In silico analysis revealed David et al., 2003; Shin et al., 2003; Gonzalo et al., 2005; that only D5Z2 possesses intact CENP-B boxes David et al., 2006; Bourgo et al., 2009). Furthermore, (Rosandic et al., 2006) (not shown), a 17 bp motif targeting of chromatin modifiers to human artificial necessary for de novo centromere formation on human chromosomes disrupts centromere function (Nakano artificial chromosomes (Ohzeki et al., 2002). Consistent et al., 2008; Cardinale et al.,2009;Bergmannet al., 2011). with these observations, immunofluorescence (IF) Epigenetic gene mis-regulation in cancer is well showed that CENP-A colocalized almost exclusively documented, reflecting aberrant patterns of both histone with D5Z2 in chromosome spreads from the HT1080 and DNA methylation as well as histone acetylation. lung cancer cell line (in 22/27 chromosome 5 examples), Some of the enzymatic pathways involved have been suggesting that a portion of D5Z2 forms the kinetochore targeted therapeutically (Rodriguez-Paredes and (Figure 1b). The remainder of D5Z2 spans the inner Esteller, 2011). In contrast, the impact of epigenetic centromere region (Figure 1b). The infrequent overlap perturbation on centromere function in human cancer of D5Z1 with CENP-A (in 4/27 chromosome 5 remains largely unexplored. The available data support examples) is likely to reflect resolution limitations due the generic model of centromere structure outlined
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