Int J Biol Sci 2020; 16(15):3002-3017. doi:10.7150/ijbs.45115

Research Paper

Poly(U) binding splicing factor 60 promotes renal cell carcinoma growth by transcriptionally upregulating telomerase reverse transcriptase

Qian Long1*, Yijun Hua1*, Liru He1*, Changlin Zhang2*, Silei Sui3, Yixin Li4, Huijuan Qiu1, Tian Tian1, Xin An1, Guangyu Luo1, Yue Yan1, Anshi Zhao1, Dingbo Shi1, Fangyun Xie1, Miao Chen1✉, Fufu Zheng5✉, Wuguo Deng1✉

1. Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.
2. The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China.
3. Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
4. Department of Clinical Oncology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, China.
5. The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
*These authors contributed equally to this article.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Citation:
Long Q, Hua Y, He L, Zhang C, Sui S, Li Y, Qiu H, Tian T, An X, Luo G, Yan Y, Zhao A, Shi D, Xie F, Chen M, Zheng F, Deng W. Poly(U) binding splicing factor 60 promotes renal cell carcinoma growth by transcriptionally upregulating telomerase reverse transcriptase. Int J Biol Sci 2020; 16(15):3002-3017. doi:10.7150/ijbs.45115. Available from http://www.ijbs.com/v16p3002.htm

File import instruction

Abstract

Background: Abnormal transcriptional upregulation of telomerase reverse transcriptase (TERT) plays a dominant role in telomerase activation in various cancers. TERT promoter mutations (TPMs) have been identified as a key mechanism in TERT upregulation. However, the mechanism of TERT upregulation in cancers with low frequency of TPMs are not fully elucidated so far.

Methods: The expression of PUF60 and TERT was detected by real-time PCR, western blot and immunohistochemistry. TERT promoter binding proteins were identified by streptavidin-agarose pulldown assay and mass spectrum (MS) analysis. The role of PUF60/TERT in renal cancer was evaluated on cell growth in vitro and in vivo.

Results: In this study, we identify the regulation mechanism of TERT in renal cell carcinoma (RCC) cells which have rare TPMs but exert significant upregulation of TERT. We found that TERT was highly expressed in RCC tumor tissues, and elevated TERT expression was associated with poor prognosis for patients. We also detected the relatively rare TPM status in both RCC tumor tissues and RCC cell lines. Mechanistically, PUF60, a RNA binding protein, was identified as a novel TERT regulator which bound to the TERT and transcriptionally upregulated TERT expression in RCC cells. The in vitro and in vivo experiments also demonstrated that PUF60 could promote RCC cell growth through activation of TERT expression in a TPM status independent way. Furthermore, we showed that there was a strong correlation of the expression of PUF60 and TERT in RCC tumor tissues and RCC cell lines, and the patients with high expression of PUF60 and TERT had significantly shorter survival.

Conclusions: Collectively, these results indicated that PUF60 transcriptionally upregulated TERT expression to promote RCC growth and progression in a TPM status independent way, suggesting that the PUF60/TERT signaling pathway may serve as potential prognostic biomarkers and therapeutic targets for RCC.

Keywords: telomerase reverse transcriptase (TERT), renal cell carcinoma (RCC), PUF60