J Cancer 2020; 11(9):2442-2452. doi:10.7150/jca.39380

Research Paper

HKR3 regulates cell cycle through the inhibition of hTERT in hepatocellular carcinoma cell lines

Sung Hoon Choi1, Kyung Joo Cho1,2, Sung Ho Yun3, Bora Jin1,2, Ha Young Lee3,4, Simon W Ro1,5, Do Young Kim1,5, Sang Hoon Ahn1,2,5, Kwang-hyub Han1,3,5, Jun Yong Park1,2,5✉

1. Yonsei Liver Center, Yonsei University College of Medicine, Seoul, Republic of Korea
2. BK21 plus project for medical science, Yonsei University College of Medicine, Seoul, Republic of Korea
3. Division of Bioconvergence Analysis, Drug & Disease Target Team, Korea Basic Science Institute (KBSI), Cheongju, Republic of Korea
4. Bio-Analysis Science, University of Science & Technology (UST), 217 Gajeong-ro, Yuseong-gu, Daejeon, Republic of Korea
5. Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea

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Citation:
Choi SH, Cho KJ, Yun SH, Jin B, Lee HY, Ro SW, Kim DY, Ahn SH, Han Kh, Park JY. HKR3 regulates cell cycle through the inhibition of hTERT in hepatocellular carcinoma cell lines. J Cancer 2020; 11(9):2442-2452. doi:10.7150/jca.39380. Available from http://www.jcancer.org/v11p2442.htm

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Abstract

Hepatocellular carcinoma is a malignant disease with improved hepatic regeneration and survival, and is activated by human telomere transferase (hTERT). hTERT is expressed during early fetal development and switched off in most adult tissues, but it becomes reactivated in HCC. The exact mechanism regulating these expression changes remains unknown during HCC progress. We evaluated the relationship between hTERT expression and human kruppel-related 3 (HKR3) and cell cycle-related factors in HCC cell lines. Following transfection for hTERT knockdown and HKR3 overexpression, proteomic and transcriptomic analyses related to hTERT were performed using liquid chromatography/mass spectrometry (LC/MS) and RNA sequencing (RNAseq) in HCC cell lines. The expression levels of hTERT, HKR3, and cell cycle-related factors were measured using western blotting, and tumor growth were evaluated via cell proliferation and cell cycle assays. Transcriptomic and proteomic analyses showed that HKR3, hTERT and cyclin-dependent kinase inhibitor 2A (CDKN2A) were correlated. Up-regulation of HKR3 expression decreased hTERT and cyclin activation and suppressed the G1/S phase of the cell cycle through CDKN2A activation. Our results suggest that HKR3 induced regulation of cell cycle through hTERT inhibition and CDKN2A activation. Our results will facilitate further exploration of the pathways regulating human telomerase activity in HCC cell lines.

Keywords: Hepatocellular carcinoma, Cell cycle, CDKN2A, hTERT, HKR3