title: Gankyrin facilitates follicle-stimulating hormone-driven ovarian cancer cell proliferation through the PI3K/AKT/HIF-1α/cyclin D1 pathway.
abstract: Gankyrin is a regulatory subunit of the 26kD proteasome complex. As a novel oncoprotein, gankyrin is expressed aberrantly in cancers from several different sites and has been shown to contribute to oncogenesis in endometrial and cervical carcinomas. Neither gankyrin's contribution to the development of epithelial ovarian cancer nor its interaction with follicle-stimulating hormone (FSH)-driven proliferation in ovarian cancer has been studied. Here we have found that gankyrin is overexpressed in ovarian cancers compared with benign ovarian cystadenomas and that gankyrin regulates FSH upregulation of cyclin D1. Importantly, gankyrin regulates PI3K/AKT signaling by downregulating PTEN. Prolonged AKT activation by FSH stimulation of the FSH receptor (FSHR) promotes gankyrin expression, which, in turn, enhances AKT activation by inhibiting PTEN. Overexpression of gankyrin decreases hypoxia inducible factor-1α (HIF-1α) protein levels, but has little effect on HIF-1α mRNA levels, which could be attributed to gankyrin mediating HIF-1α protein stability via the ubiquitin-proteasome pathway. Reduction in HIF-1α protein stability led to attenuation of the binding with cyclin D1 promoter, resulted in abolishment of the negative regulation of cyclin D1 by HIF-1α, which promotes proliferation of ovarian cancer cells. Our results document that gankyrin regulates HIF-1α protein stability and cyclin D1 expression, ultimately mediating FSH-driven ovarian cancer cell proliferation.
authors.affiliation: Department of Obstetrics and Gynecology, Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Obstetrics and Gynecology, Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: M
authors.initials: M
authors.lastname: Bai
authors.affiliation: Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China.
authors.forename: C
authors.initials: C
authors.lastname: Ning
authors.affiliation: Department of Obstetrics and Gynecology, Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: B
authors.initials: B
authors.lastname: Xie
authors.affiliation: Department of Obstetrics and Gynecology, Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: H
authors.initials: H
authors.lastname: Liao
authors.affiliation: Department of Neuropathology, Huashan Hospital of Fudan University, Shanghai, China.
authors.forename: J
authors.initials: J
authors.lastname: Xiong
authors.affiliation: Department of Pathology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China.
authors.forename: X
authors.initials: X
authors.lastname: Tao
authors.affiliation: Department of Obstetrics and Gynecology, Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: D
authors.initials: D
authors.lastname: Yan
authors.affiliation: Department of Obstetrics and Gynecology, Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: X
authors.initials: X
authors.lastname: Xi
authors.affiliation: Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China.
authors.forename: X
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China.|Department of Experimental Therapeutics, MD Anderson Cancer Center, The University of Texas, Houston, TX, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Experimental Therapeutics, MD Anderson Cancer Center, The University of Texas, Houston, TX, USA.
authors.forename: R C
authors.initials: RC
authors.lastname: Bast
authors.affiliation: Department of Obstetrics and Gynecology, Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Obstetrics and Gynecology, Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Department of Pathology, University of Arizona College of Medicine, Tucson, AZ, USA.|Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: W
authors.initials: W
authors.lastname: Zheng
mesh_terms: D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism*; D005260:Female; D005640:Follicle Stimulating Hormone / Q000494:pharmacology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D009375:Neoplasms, Glandular and Epithelial / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D054875:Ubiquitination / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C403591:PSMD10 protein, human; D011518:Proto-Oncogene Proteins; D019938:Cyclin D1; D005640:Follicle Stimulating Hormone; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D046988:Proteasome Endopeptidase Complex