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BPTF promotes hepatocellular carcinoma growth by modulating hTERT signaling and cancer stem cell traits
Xinrui Zhaoa,1, Fufu Zhengc,1, Yizhuo Lib,1, Jiaojiao Haoa,1, Zhipeng Tanga, Chunfang Tiana, Qian Yanga, Tianhua Zhua, Chaoliang Diaoa, Changlin Zhangb, Manyu Chena, Sheng Hua, Ping Guoa, Lizhi Zhangd, Yina Liaoa, Wendan Yua, Miao Chenb, Lijuan Zoua, Wei Guoa, , Wuguo Dengb, a Institute of Cancer Stem Cell & The Second Affiliated Hospital, Dalian Medical University, Dalian, China b Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China c The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China d The First Affiliated Hospital, Dalian Medical University, Dalian, China
Cancer stem cell
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 me-chanism 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 CAY10566 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 sup-pression 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.
Hepatocellular carcinoma (HCC) is one of the most common ma-lignancies, and ranks as the fifth and eighth leading cause of cancer-related death in men and women respectively . The preferred and most effective therapy option for HCC remains surgical resection, and the other treatments include transplantation, chemotherapy, radio-therapy and biotherapy [2–4]. However, the high recurrence rate and metastatic rate still forms severe challenges in HCC treatment. Cancer stem-like cells (CSC) are considered as a cell population which  sustain cell immortalization, promote cell self-renewal, and are re-sponsible for the tumor metastasis, relapse and chemoresistance [6–8].
Therefore, the increased understanding of the molecular mechanisms that regulate cellular unlimited proliferation and stemness maintenance in HCC progression and the discovery and identification of new can-didate targets responsible for HCC initiation and development might open up the new avenues to accelerate the development of novel di-agnostic and therapeutic strategies to improve the prognosis for pa-tients with HCC.
Nucleosome remodeling factor (NURF) complex exists in nearly all eukaryotic species by displaying its effect via catalyzing ATP-dependent nucleosome sliding and facilitating transcription mediated by chro-matin [9,10]. As the largest subunit of the NURF chromatin remodeling complex, bromodomain PHD finger transcription factor (BPTF) is
Correspondence to: Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China.
Correspondence to: Sun Yat-sen University Cancer Center, Guangzhou 510060, China. E-mail addresses: [email protected] (W. Guo), [email protected] (W. Deng).
1 These authors contributed equally to this manuscript.
critical for epigenetically regulating DNA accessibility and gene ex-pression . It is also reported to be essential in embryonic develop-ment [11,12]. BPTF has recently been found to affect tumor progres-sion, especially melanoma survival, by activating oncogenic signaling directly or by synergizing with other key protein factors, such as c-MYC [13–15]. Its prognostic significance associated with EMT marker in colorectal carcinoma and HCC was also mentioned [16,17]. Never-theless, to date, its precise function and molecular mechanisms in HCC development, especially in the maintenance of HCC cancer stem cell-like straits, are still poorly understood.