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

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.

The Revelation of Continuously Organized, Co-Overexpressed Protein-Coding Genes with Roles in Cellular Communications in Breast Cancer

“…In contrast, PUF60 overexpression in renal cancer cells stimulates telomerase reverse transcriptase (TERT) transcription due to PIF60’s binding to the TERT promoter [ 69 ]. PUF60 also contributes to breast cancer progression via the PUF60-dependent downregulation of PTEN, stimulating the PI3-kinase pathway [ 70 ].…”

Targeting PUF60 prevents tumor progression by retarding mRNA decay of oxidative phosphorylation in ovarian cancer

“…PUF60 knockdown significantly decreased the proliferation in vitro and in vivo [ 35 ]. In renal cell carcinoma (RCC) cells, PUF60 promote cell growth and the patients with high expression of PUF60 had significantly shorter survival [ 16 ]. In our study, PUF60 is highly expressed in OC and its upregulation predicts a poor prognosis, and PUF60 promotes the proliferation and migration of OC cells both in vitro and in vivo, which is consistent with other tumors.…”

“…Moreover, the relative abundance of PUF60 influences the choice of alternative splice sites [ 8 ]. It has been reported that PUF60 is overexpressed in various cancers, including bladder cancer [ 9 ], colon cancer [ 10 ], hepatocellular carcinoma [ 11 ], non-small cell lung cancer [ 12 ], breast cancer [ 13 , 14 ], esophageal cancer [ 15 ] and renal cell carcinoma [ 16 ], and its overexpression is closely related to its development and progression. Studies have shown through integrated copy number and expression analysis that PUF60 may be a novel potential driver [ 17 ].…”

Genetic association study of TERT gene variants with chronic kidney disease susceptibility in the Chinese population

“…For example, a study Long et al. demonstrated that the upregulation of TERT promotes the growth of renal cell carcinoma (RCC) [ 15 ]. In addition, the TERT locus genotypes of rs2736100-CC/CA and rs2736098-AA have been associated with shorter survival in patients with RCC, as reported by Ma et al.…”