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Effects of Rearrangement and Allelic Exclusion of JJAZ1/SUZ12 on Cell Proliferation and Survival

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Effects of Rearrangement and Allelic Exclusion of JJAZ1/SUZ12 on Cell Proliferation and Survival Effects of rearrangement and allelic exclusion of JJAZ1/SUZ12 on cell proliferation and survival Hui Li*, XianYong Ma*, Jinglan Wang*, Jason Koontz†, Marisa Nucci‡, and Jeffrey Sklar*§ *Department of Pathology, Yale University School of Medicine, New Haven, CT 06520; †Department of Medicine, Duke University, Durham, NC 27708; and ‡Division of Molecular Oncology, Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115 Communicated by Sherman M. Weissman, Yale University School of Medicine, New Haven, CT, October 22, 2007 (received for review August 9, 2007) Polycomb group genes (PcGs) have been implicated in cancer based that SNs do not show invasion of surrounding tissues within the on altered levels of expression observed in certain tumors and the uterus and are therefore considered benign. In contrast, ESSs show behavior of cultured cells containing inserted PcG transgenes. Endo- invasion and are malignant. metrial stromal tumors provide evidence for a direct causal relation- By using cytogenetics and molecular methods of detection, ship because they contain several chromosomal translocations and approximately one-half of ESSs have been shown to contain a resultant gene fusions involving PcGs, the most common of which specific recurrent chromosomal translocation, the t(7;17)(p15;q21) joins portions of the JAZF1 gene to the PcG JJAZ1/SUZ12. We show (11–15). More recently, this translocation has been found in each here that both benign and malignant forms of this tumor have the case of SNs analyzed, although the total number of such tumors JAZF1–JJAZ1 fusion but only the malignant form also exhibits exclu- tested is necessarily small because of the rarity of these neoplasms sion of the unrearranged JJAZ1 allele. To evaluate the effects of both (12). Recombination of DNA at the site of breakage and rejoining the JJAZ1/SUZ12 fusion and allelic exclusion on functions related to in the translocation results in the fusion of two genes, JAZF1 and cell growth, we studied HEK293 cells that were modified with respect JJAZ1, and production of a chimeric RNA in which the first three to JJAZ1 expression. We found that the JAZF1–JJAZ1 fusion restored exons (from five total) of JAZF1 are joined to the last 15 (from 16) levels of the polycomb protein EZH2 and histone 3 lysine 27 trim- of JJAZ1 (11). Neither the reciprocal RNA nor its protein product ethylation, which were reduced by knockdown of endogenous JJAZ1. has been identified within ESSs. At the same time, the presence of JAZF1–JJAZ1 markedly inhibited Little is known about the function of JAZF1, although there is apoptosis and induced above normal proliferation rates, although the one report of coimmunoprecipitation of the JAZF1 protein with latter effect occurred only when normal JJAZ1 was suppressed. Our the TAK1 orphan nuclear receptor (16). On the other hand, several findings suggest a genetic pathway for progression of a benign years after the discovery of JJAZ1 through its alteration by the precursor to a sarcoma involving increased cell survival associated t(7;17), its ortholog in Drosophila was identified to be the gene with acquisition of a PcG rearrangement, followed by accelerated mutated in flies with the SuZ12 phenotype (17). Since then, the cellular proliferation upon allelic exclusion of the unrearranged copy JJAZ1/SUZ12 protein has been shown to be an essential compo- of that gene. Furthermore, these results indicate the likely functional nent, along with the proteins EZH2 and EED, of the polycomb importance of allelic exclusion of genes disrupted by chromosomal repression complex 2 (PRC2) (18, 19), which is responsible for the translocations, as seen in a variety of other cancers. methylation of lysines 9 and 27 in histone 3 (20–28). JJAZ1 chromosomal translocation ͉ endometrial stromal tumor ͉ polycomb group The mechanism by which altered presumably contributes gene ͉ chromatin remodeling ͉ apoptosis to the neoplastic phenotype in SNs and ESSs is not known, nor is it understood what distinguishes the malignant behavior of ESSs from the benign behavior of SNs. Here we report that expression olycomb group genes (PcGs) encode proteins that act in of the unrearranged allele of JJAZ1 in ESSs with the t(7;17) is Pmultimeric complexes to methylate histones, leading to chro- suppressed, as opposed to the unrearranged allele in SNs, in which matin remodeling, regional compaction of the chromatin, and it is fully active. Difficulties in the stable insertion of transgenes into suppression of transcription from genes associated with these cultured endometrial stromal cells have hampered study of JJAZ1 regions (1, 2). Increased levels of polycomb proteins have been alterations in the normal counterpart to cells of ESS; however, detected in a variety of human cancers (3, 4), often correlated with introduction of a JAZF1–JJAZ1 expression vector into cultured 293 more aggressive clinical behavior (5, 6). Aberrant coexpression of cells produces a number of significant effects on the growth various PcGs has been noted in the malignant cells of certain properties of these cells. Besides restoring to near normal levels the cancers, and neoplastic transformation of cells in culture has been achieved by over-expression of PcGs from inserted cDNA se- reduced amounts of EZH2 and total trimethyl histone 3 lysine 27 quences (7). Although such observations imply a role for PcGs in (H3K27) seen when JJAZ1 is deficient in these cells, introduction the transformed phenotype of neoplastic cells, the proximity of of a JAZF1–JJAZ1 vector into cells promotes proliferation of these abnormal levels of Polycomb proteins to the primary changes in the cells. This effect depends on suppression of the endogenous JJAZ1, cell that control neoplastic behavior is unclear. because in the presence of normal JJAZ1 expression, JAZF1–JJAZ1 Endometrial stromal tumors provide evidence for a primary role decreases proliferation. However, expression of JAZF1–JJAZ1 with of PcGs in neoplastic cell behavior because these tumors contain a or without suppression of JJAZ1 protects cells from serum depri- series of rearrangements of DNA within several PcGs. These vation and hypoxia-induced apoptosis. tumors arise in the mesenchymal tissue that underlies the surface epithelium of the uterine cavity and surrounds endometrial glands Author contributions: H.L. and J.S. designed research; H.L., X.M., and J.W. performed formed by invaginations of the surface epithelium. Three major research; J.K. and M.N. contributed new reagents/analytic tools; H.L. and J.S. analyzed data; types of tumors derive from this tissue: endometrial stromal nodules and H.L., M.N., and J.S. wrote the paper. (SNs), endometrial stromal sarcomas (ESSs), and undifferentiated The authors declare no conflict of interest. uterine sarcomas (8–10). Whereas the latter tumor shows highly §To whom correspondence should be addressed at: Department of Pathology, Yale Uni- atypical cytological features, the other two tumors are both com- versity School of Medicine, New Haven, CT 06520. E-mail: [email protected]. posed of cells that histologically resemble the cells of normal This article contains supporting information online at www.pnas.org/cgi/content/full/ endometrial stroma during the proliferative phase of the menstrual 0709986104/DC1. MEDICAL SCIENCES cycle (8–10). The principal difference between these two tumors is © 2007 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0709986104 PNAS ͉ December 11, 2007 ͉ vol. 104 ͉ no. 50 ͉ 20001–20006 Downloaded by guest on October 2, 2021 A A B B Fig. 1. Analysis of JJAZ1 protein and mRNA in ESS cell lines. (A) Western blot of cell lines analyzed with anti-JJAZ1 antiserum. Cases 1, 2, and 3 are primary ESS cell lines. Chr, S2, and S3 represent the chromatin-enriched cell fraction, the soluble cytoplasmic fraction, and the soluble nuclear fraction, respectively. (B) Real-time RT-PCR for JJAZ1 mRNA. The amount of WT allele JJAZ1 mRNA was compared with the amount of ␤-actin mRNA. ESS1 is an ESS cell line derived from a tumor lacking the t(7;17). Fig. 2. Analysis of JAZF1 protein and mRNA in ESS cell lines. (A) Real-time RT-PCR for JAZF1 mRNA. The amount of WT JJAZ1 mRNA was normalized Results against the amount of ␤-actin mRNA. (B) Western blot of cell lines analyzed Suppression of the Unrearranged JJAZ1 Allele in ESSs with the t(7;17). with anti-JAZF1 antiserum. Cases 1 and 2 are primary ESS cell lines. Expression of JJAZ1 was analyzed by Western blots, which was performed with anti-JJAZ1 antibody generated by us against JJAZ1 polypeptides. A higher band, corresponding to the predicted mo- ments were unsuccessful because of failure to insert exogenous lecular weight of the amino-terminal JAZF1 to carboxyl-terminal sequences into these cells with retroviral vectors. Although initial JJAZ1 chimeric protein, was observed in the three primary tumor infection proved possible, transduced sequences were rapidly elim- cell lines derived from ESSs. These three tumors have been inated from the cells. Moreover, numerous attempts at transfecting demonstrated to harbor the t(7;17) translocation by conventional these cells by using a variety of agents to promote uptake of DNA cytogenetics, fluorescence in situ hybridization (FISH), and RT- plasmids did not yield cells in which transfected DNA was stably PCR amplification of RNA sequences across the site of fusion in the integrated into the host cell genomes. Consequently, we conducted JAZF1–JJAZ1 transcription product. Additionally, normal JJAZ1 further experiments by using 293 cells. Specifically, by using these was almost undetectable in these three cases (Fig. 1A). To confirm cells, we sought to determine the influence of the JAZF1–JJAZ1 this finding and check whether suppression of JJAZ1 occurs at a pretranslational level, we performed RT-PCR with primers de- signed to amplify only the WT allele of JJAZ1 by annealing to sequences of JJAZ1 RNA (and its complement) 5Ј of the site of fusion of JAZF1 and JJAZ1 in the chimeric transcript.
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