title: O-linked N-acetylglucosamine transferase promotes cervical cancer tumorigenesis through human papillomaviruses E6 and E7 oncogenes.
abstract: O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) increases O-GlcNAc modification (O-GlcNAcylation), and transcriptional co-regulator host cell factor 1 (HCF-1) is one of OGT targets. High-risk Human Papillomaviruses (HPVs) encode E6 and E7 oncoproteins, which promote cervical cancer. Here, we tested whether O-GlcNAc modification of HCF-1 affects HPV E6 and E7 expressions and tumorigenesis of cervical cancer. We found that depleting OGT with OGT-specific shRNA significantly decreased levels of E6 and E7 oncoproteins, and cervical cancer tumorigenesis, while OGT overexpression greatly increased levels of E6 and E7 oncoproteins. Notably, OGT overexpression caused dose-dependent increases in the transcriptional activity of E6 and E7, and this activity was decreased when HCF-1 was depleted with HCF-1-specific siRNA. Moreover, OGT depletion reduced proliferation, invasion, and metastasis in cervical cancer cells. Further, high glucose enhanced the interaction between OGT and HCF-1, paralleling increased levels of E6 and E7 in cervical cancer cells. Most importantly, we found that reducing OGT in HeLa cells caused decreased tumor growth in vivo. These findings identify OGT as a novel cellular factor involved in E6 and E7 expressions and cervical cancer tumorigenesis, suggesting that targeting OGT in cervical cancer may have potential therapeutic benefit.
authors.affiliation: Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Gyeongnam, Republic of Korea.
authors.forename: Minjun
authors.initials: M
authors.lastname: Kim
authors.affiliation: Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Gyeongnam, Republic of Korea.
authors.forename: Yoon Sook
authors.initials: YS
authors.lastname: Kim
authors.affiliation: Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Gyeongnam, Republic of Korea.
authors.forename: Hwajin
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Obstetrics and Gynecology, Gyeongsang National University School of Medicine, Jinju, Gyeongnam, Republic of Korea.
authors.forename: Min Young
authors.initials: MY
authors.lastname: Kang
authors.affiliation: Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Gyeongnam, Republic of Korea.
authors.forename: Jeongsook
authors.initials: J
authors.lastname: Park
authors.affiliation: Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Gyeongnam, Republic of Korea.
authors.forename: Dong Hoon
authors.initials: DH
authors.lastname: Lee
authors.affiliation: Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Gyeongnam, Republic of Korea.
authors.forename: Gu Seob
authors.initials: GS
authors.lastname: Roh
authors.affiliation: Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Gyeongnam, Republic of Korea.
authors.forename: Hyun Joon
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Gyeongnam, Republic of Korea.
authors.forename: Sang Soo
authors.initials: SS
authors.lastname: Kang
authors.affiliation: Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Gyeongnam, Republic of Korea.
authors.forename: Gyeong Jae
authors.initials: GJ
authors.lastname: Cho
authors.affiliation: Department of Obstetrics and Gynecology, Gyeongsang National University School of Medicine, Jinju, Gyeongnam, Republic of Korea.
authors.forename: Ji Kwon
authors.initials: JK
authors.lastname: Park
authors.affiliation: Department of Integrated OMICS for Biomedical Science, Graduate School, Yonsei University, Seoul, Republic of Korea.
authors.forename: Jin Won
authors.initials: JW
authors.lastname: Cho
authors.affiliation: Department of Obstetrics and Gynecology, Gyeongsang National University School of Medicine, Jinju, Gyeongnam, Republic of Korea.
authors.forename: Jeong Kyu
authors.initials: JK
authors.lastname: Shin
authors.affiliation: Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Gyeongnam, Republic of Korea.
authors.forename: Wan Sung
authors.initials: WS
authors.lastname: Choi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D006367:HeLa Cells; D051863:Host Cell Factor C1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D008875:Middle Aged; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics / Q000378:metabolism*; D009856:Oncogene Proteins, Viral / Q000378:metabolism*; D050725:Papillomavirus E7 Proteins / Q000378:metabolism; D034622:RNA Interference; D012097:Repressor Proteins / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D004268:DNA-Binding Proteins; C068651:E6 protein, Human papillomavirus type 16; C052603:E6 protein, Human papillomavirus type 18; C052633:E7 protein, Human papillomavirus type 18; C497692:HCFC1 protein, human; D051863:Host Cell Factor C1; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; C059731:oncogene protein E7, Human papillomavirus type 16; D017351:N-Acetylglucosaminyltransferases; C063057:UDP-N-acetylglucosamine-peptide beta-N-acetylglucosaminyltransferase
keywords: E6 and E7; O-GlcNAcylation; OGT; host cell factor 1