Abstract
Hepatocellular carcinoma (HCC) has a high mortality rate and lacks an effective therapeutic target. Elevated expression of human telomerase reverse transcriptase (TERT) is an important hallmark in cancers, but the mechanism by which TERT is activated differentially in cancers is poorly understood. Here, we have identified nuclear receptor coactivator-3 (NCOA3) as a new modulator of TERT expression and tumor growth in HCC. NACO3 specifically binds to the TERT promoter at the -234 to -144 region and transcriptionally activates TERT expression. NCOA3 promotes HCC cell growth and tumor progression in vitro and in vivo through upregulating the TERT signaling. Knockdown of NACO3 suppresses HCC cell viability and colony formation, whereas TERT overexpression rescues this suppression. NCOA3 interacts with and recruits SP1 binding on the TERT promoter. Knockdown of NCOA3 also inhibits the expression of the Wnt signaling-related genes but has no effect on the Notch signaling-targeting genes. Moreover, NCOA3 is positively correlated with TERT expression in HCC tumor tissues, and high expression of both NCOA3 and TERT predicts a poor prognosis in HCC patients. Our findings indicate that targeting the NCOA3-SP1-TERT signaling axis may benefit HCC patients.
Highlights
Hepatocellular carcinoma (HCC) is one of the most common cancers and a leading cause of cancer death worldwide[1]
We found that nuclear receptor coactivator-3 (NCOA3), a potential candidate, differentially bound to the telomerase reverse transcriptase (TERT) promoter in HCC cells (Fig. 1A, Fig. S1A)
A Chromatin immunoprecipitation (ChIP) assay was performed to confirm that NCOA3 bound to TERT promoter in LO2 and HCC cells, and the results showed that NCOA3 had much stronger binding at the endogenous TERT promoter in HCC cells compared to LO2 cells (Fig. 1C)
Summary
Hepatocellular carcinoma (HCC) is one of the most common cancers and a leading cause of cancer death worldwide[1]. The molecular mechanisms leading to the development of HCC are TERT is the catalytic component of telomerase and extends telomeres with its RNA partner (telomerase RNA component). TERT can directly regulate the various hallmarks of cancer, which include sustaining proliferative signaling, evading growth suppressors, inducing angiogenesis, resisting cell death, activating invasion and metastasis, tumor-promoting inflammation, and enabling replicative immortality[8]. What’s more, TERT acts as a regulator of the transcription of genes involved in cancer cell growth and proliferation, independently of its role in telomeres[9].
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
