title: SUZ12 promotes human epithelial ovarian cancer by suppressing apoptosis via silencing HRK.
abstract: Epithelial ovarian cancer (EOC) ranks first as the cause of death for gynecological cancers in the United States. SUZ12 is a component of the polycomb repressive complex 2 (PRC2) and is essential for PRC2-mediated gene silencing by generating trimethylation on lysine 27 residue of histone H3 (H3K27Me3). The role of SUZ12 in EOC has never been investigated. Here, we show that SUZ12 is expressed at significantly higher levels in human EOC (n = 117) compared with either normal human ovarian surface epithelium (n = 35, P < 0.001) or fallopian tube epithelium (n = 15, P < 0.001). There is a positive correlation between expression of SUZ12 and EZH2 in human EOC (P < 0.001). In addition, expression of SUZ12 positively correlates with Ki67, a marker of cell proliferation (P < 0.001), and predicts shorter overall survival (P = 0.0078). Notably, knockdown of SUZ12 suppresses the growth of human EOC cells in vitro and in vivo in both orthotopic and subcutaneous xenograft EOC models. In addition, SUZ12 knockdown decreases the levels of H3K27Me3 and triggers apoptosis of human EOC cells. Mechanistically, we identified Harakiri (HRK), a proapoptotic gene, as a novel SUZ12 target gene, and showed that HRK upregulation mediates apoptosis induced by SUZ12 knockdown in human EOC cells. In summary, we show that SUZ12 promotes the proliferation of human EOC cells by inhibiting apoptosis and HRK is a novel SUZ12 target gene whose upregulation contributes to apoptosis induced by SUZ12 knockdown.
authors.affiliation: Gene Expression and Regulation Program, The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.forename: Qi
authors.initials: Q
authors.lastname: Cai
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
authors.forename: Vinod
authors.initials: V
authors.lastname: Vathipadiekal
authors.forename: Zachary C
authors.initials: ZC
authors.lastname: Dobbin
authors.forename: Tianyu
authors.initials: T
authors.lastname: Li
authors.forename: Xiang
authors.initials: X
authors.lastname: Hua
authors.forename: Charles N
authors.initials: CN
authors.lastname: Landen
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Birrer
authors.forename: Margarita
authors.initials: M
authors.lastname: Sánchez-Beato
authors.forename: Rugang
authors.initials: R
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D000077216:Carcinoma, Ovarian Epithelial; D048708:Cell Growth Processes / Q000235:genetics; D045744:Cell Line, Tumor; D000071221:Enhancer of Zeste Homolog 2 Protein; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D009363:Neoplasm Proteins; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D063151:Polycomb Repressive Complex 2 / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D046888:Tissue Array Analysis; D014157:Transcription Factors; D014162:Transfection
chemical_list: D051017:Apoptosis Regulatory Proteins; C484586:HRK protein, human; D019394:Ki-67 Antigen; D009363:Neoplasm Proteins; C430461:SUZ12 protein, human; D014157:Transcription Factors; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2