O-linked N-acetylglucosamine transferase promotes cervical cancer tumorigenesis through human papillomaviruses E6 and E7 oncogenes
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Minjun Kim1,*, Yoon Sook Kim1,*, Hwajin Kim1,*, Min Young Kang2, Jeongsook Park1, Dong Hoon Lee1, Gu Seob Roh1, Hyun Joon Kim1, Sang Soo Kang1, Gyeong Jae Cho1, Ji Kwon Park2, Jin Won Cho3, Jeong Kyu Shin2, Wan Sung Choi1
1Department of Anatomy and Convergence Medical Science, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Gyeongnam, Republic of Korea
2Department of Obstetrics and Gynecology, Gyeongsang National University School of Medicine, Jinju, Gyeongnam, Republic of Korea
3Department of Integrated OMICS for Biomedical Science, Graduate School, Yonsei University, Seoul, Republic of Korea
*These authors have contributed equally to this work
Wan Sung Choi, email: [email protected]
Jeong Kyu Shin, email: [email protected]
Keywords: O-GlcNAcylation, host cell factor 1, OGT, E6 and E7
Received: December 18, 2015 Accepted: June 01, 2016 Published: June 16, 2016
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.
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