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

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.

Metformin inhibits MAPK signaling and rescues pancreatic aquaporin 7 expression to induce insulin secretion in type 2 diabetes mellitus

“…Lentivirus infection for the INS-1 cells was conducted as described previously ( 43 ). Briefly, to establish INS-1 cells with stable AQP7 overexpression, the Ubi-AQP7-MCS-3FLAG-SV40-EGFP-IRES-puromycin lentivirus, which encodes a full-length rat AQP7 gene, and the Ubi-MCS-3FLAG-SV40-EGFP-IRES-puromycin as empty vector control were transfected into INS-1 cells, and stable clones with AQP7 overexpression were selected after 2 weeks with 0.5 to 2 μg/ml puromycin.…”

PFKFB4 is overexpressed in clear-cell renal cell carcinoma promoting pentose phosphate pathway that mediates Sunitinib resistance

“…It was found overexpressed in 60 % breast cancer patients, leading to tamoxifen resistance and worse clinical outcome, while the NCOA3 deficiency could suppress the tumor initiation and progression in mice model with breast cancer [ 32 ]. Via regulating the telomerase reverse transcriptase (TERT) signaling, NCOA3 promoted cell viability and colony formation in hepatocellular carcinoma cells, and high expression of NCOA3 had worse prognosis [ 33 ]. Dusgupta et al [ 26 ] unveiled that PFKFB4 phosphorylated SRC-3(also known as NCOA3) to drive glucose flux towards the pentose phosphate pathway, demonstrating the correlation between metabolic reprogramming and transcriptional regulation.…”

Conditional ERK3 overexpression cooperates with PTEN deletion to promote lung adenocarcinoma formation in mice

“…Akt phosphorylates SP1, thereby stimulating SP1 transcriptional activity [43,44]. In addition, SP1 transcriptional activity is also regulated by its coactivators such as SRC-3 [45,46]. We have reported in our previous study that ERK3 phosphorylates SRC-3, which stimulates the interaction of SRC-3 with SP1 and their transcriptional activity in VEGFR2 gene transcription [36].…”