Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.
Institute of Neuroscience and Department of Neurology of the Second Affiliated Hospital of Guangzhou Medical University, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China.
Cell Death Dis. 2020 Nov 25;11(11):1011. doi: 10.1038/s41419-020-03218-x.
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.
肝细胞癌（HCC）死亡率高，缺乏有效的治疗靶点。人端粒酶逆转录酶（hTERT）的高表达是癌症的一个重要标志，但 hTERT 在癌症中差异激活的机制尚不清楚。在这里，我们鉴定出核受体共激活因子 3（NCOA3）是 HCC 中 hTERT 表达和肿瘤生长的新调节剂。NCOA3 特异性结合 hTERT 启动子的-234 至-144 区域，并转录激活 hTERT 表达。NCOA3 通过上调 hTERT 信号促进 HCC 细胞在体外和体内的生长和肿瘤进展。敲低 NCOA3 抑制 HCC 细胞活力和集落形成，而 hTERT 过表达可挽救这种抑制作用。NCOA3 与 TERT 启动子上的 SP1 结合并募集 SP1。敲低 NCOA3 也抑制 Wnt 信号相关基因的表达，但对 Notch 信号靶向基因没有影响。此外，NCOA3 在 HCC 肿瘤组织中与 hTERT 表达呈正相关，NCOA3 和 hTERT 的高表达预示着 HCC 患者预后不良。我们的研究结果表明，靶向 NCOA3-SP1-hTERT 信号轴可能有益于 HCC 患者。
