Targeting the NCOA3-SP1-TERT axis for tumor growth in hepatocellular carcinoma

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Hepatocellular carcinoma (HCC) presents a significant mortality challenge with limited therapeutic options.
• Elevated human telomerase reverse transcriptase (TERT) expression is a known cancer hallmark, but its activation mechanisms remain unclear.
• Understanding novel regulators of TERT is crucial for developing targeted HCC therapies.

Purpose of the Study:

• To identify novel modulators of TERT expression and tumor growth in HCC.
• To elucidate the mechanism by which nuclear receptor coactivator-3 (NCOA3) influences TERT activity.
• To assess the therapeutic potential of targeting the NCOA3-TERT axis in HCC.

Main Methods:

• Investigated NCOA3's role in TERT promoter binding and transcriptional activation using molecular biology techniques.
• Assessed the impact of NCOA3 modulation on HCC cell growth, viability, and tumor progression in vitro and in vivo.
• Analyzed the interaction between NCOA3, SP1, and the TERT promoter.
• Examined the correlation between NCOA3, TERT expression, and patient prognosis in HCC tumor tissues.

Main Results:

• NCOA3 directly binds to the TERT promoter (-234 to -144 region) and transcriptionally activates TERT expression.
• NCOA3 promotes HCC cell proliferation and tumor progression by upregulating TERT signaling.
• NCOA3 interacts with SP1, facilitating its binding to the TERT promoter.
• NCOA3 knockdown inhibits Wnt signaling and HCC cell viability, effects rescued by TERT overexpression.
• NCOA3 expression positively correlates with TERT levels in HCC tissues, predicting poor prognosis.

Conclusions:

• NCOA3 is a novel activator of TERT expression and a promoter of HCC growth.
• The NCOA3-SP1-TERT signaling axis represents a potential therapeutic target for hepatocellular carcinoma.
• Targeting NCOA3 may offer a promising strategy for improving outcomes in HCC patients.