BPTF promotes hepatocellular carcinoma growth by modulating hTERT signaling and cancer stem cell traits.
BPTF promotes hepatocellular carcinoma growth by modulating hTERT signaling and cancer stem cell traits.
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BPTF 通过调节 hTERT 信号传导和癌症干细胞特征促进肝细胞癌生长
DOI：
10.1016/j.redox.2018.10.018
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发表时间：
2019-01
期刊：
影响因子：
11.4
通讯作者：
Deng W
中科院分区：
文献类型：
--
作者：
Zhao X;Zheng F;Li Y;Hao J;Tang Z;Tian C;Yang Q;Zhu T;Diao C;Zhang C;Chen M;Hu S;Guo P;Zhang L;Liao Y;Yu W;Chen M;Zou L;Guo W;Deng W
溴域PHD指转录因子(BPTF)是核小体重塑因子(NURF)复合体的核心亚单位，在染色质重塑中起重要作用。然而，其在肝细胞癌生长中的确切功能和分子机制尚不清楚。在这里，我们展示了BPTF在肝细胞癌进展中的促肿瘤作用。与正常肝细胞和正常肝组织相比，BPTF在肝癌细胞和肿瘤组织中高表达。BPTF基因敲除抑制了肝癌细胞的细胞增殖、集落形成和干细胞样特性。此外，BPTF基因敲除有效地敏化了化疗药物的抗肿瘤作用，并诱导了更多的肝癌细胞凋亡。一贯地，在异种移植小鼠模型中，BPTF的敲除也抑制了肿瘤的生长和转移，同时抑制了肿瘤干细胞(CSC)相关的蛋白标记物。此外，机制研究表明，BPTF的促肿瘤作用是通过转录调控人端粒酶逆转录酶(HTERT)的表达来实现的。此外，我们还发现BPTF高表达的肝细胞癌患者hTERT高表达，BPTF或hTERT的高表达水平与肝癌患者的恶性程度和预后不良呈正相关。总之，我们的结果表明，BPTF通过靶向hTERT促进了肝癌的生长，并提示BPTF-hTERT轴可能是一种新的、潜在的肝癌治疗靶点。
Bromodomain PHD finger transcription factor (BPTF), a core subunit of nucleosome-remodeling factor (NURF) complex, plays an important role in chromatin remodeling. However, its precise function and molecular mechanism involved in hepatocellular carcinoma (HCC) growth are still poorly defined. Here, we demonstrated the tumor-promoting role of BPTF in HCC progression. BPTF was highly expressed in HCC cells and tumor tissues of HCC patients compared with normal liver cells and tissues. Knockdown of BPTF inhibited cell proliferation, colony formation and stem cell-like traits in HCC cells. In addition, BPTF knockdown effectively sensitized the anti-tumor effect of chemotherapeutic drugs and induced more apoptosis in HCC cells. Consistently, knockdown of BPTF in a xenograft mouse model also suppressed tumor growth and metastasis accompanied by the suppression of cancer stem cells (CSC)-related protein markers. Moreover, the mechanism study showed that the tumor-promoting role of BPTF in HCC was realized by transcriptionally regulating the expression of human telomerase reverse transcriptase (hTERT). Furthermore, we found that HCC patients with high BPTF expression displayed high hTERT expression, and high BPTF or hTERT expression level was positively correlated with advanced malignancy and poor prognosis in HCC patients. Collectively, our results demonstrate that BPTF promotes HCC growth by targeting hTERT and suggest that the BPTF-hTERT axis maybe a novel and potential therapeutic target in HCC.
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