BPTF inhibition antagonizes colorectal cancer progression by transcriptionally inactivating Cdc25A
Ping Guo,
Shijia Zu,
Shilong Han,
Wendan Yu,
Guoqing Xue,
Xiaona Lu,
Hua Lin,
Xinrui Zhao,
Haibo Lu,
Chunyu Hua,
Xinyu Wan,
Liyuan Ru,
Ziyue Guo,
Hanxiao Ge,
Kuan Lv,
Guohui Zhang,
Wuguo Deng,
Cheng Luo,
Wei Guo
Affiliations
Ping Guo
Institute of Cancer Stem Cells, Dalian Medical University, Dalian, 116044, China
Shijia Zu
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; China University of Chinese Academy of Sciences, Beijing, 100049, China
Shilong Han
Institute of Cancer Stem Cells, Dalian Medical University, Dalian, 116044, China
Wendan Yu
Institute of Cancer Stem Cells, Dalian Medical University, Dalian, 116044, China
Guoqing Xue
Institute of Cancer Stem Cells, Dalian Medical University, Dalian, 116044, China
Xiaona Lu
Institute of Cancer Stem Cells, Dalian Medical University, Dalian, 116044, China
Hua Lin
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
Xinrui Zhao
Institute of Cancer Stem Cells, Dalian Medical University, Dalian, 116044, China
Haibo Lu
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, China
Chunyu Hua
Institute of Cancer Stem Cells, Dalian Medical University, Dalian, 116044, China
Xinyu Wan
Institute of Cancer Stem Cells, Dalian Medical University, Dalian, 116044, China
Liyuan Ru
Institute of Cancer Stem Cells, Dalian Medical University, Dalian, 116044, China
Ziyue Guo
Institute of Cancer Stem Cells, Dalian Medical University, Dalian, 116044, China
Hanxiao Ge
Institute of Cancer Stem Cells, Dalian Medical University, Dalian, 116044, China
Kuan Lv
Institute of Cancer Stem Cells, Dalian Medical University, Dalian, 116044, China
Guohui Zhang
Institute of Cancer Stem Cells, Dalian Medical University, Dalian, 116044, China
Wuguo Deng
Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, 510060, China; Corresponding author. Sun Yat-sen University Cancer Center, Guangzhou, China.
Cheng Luo
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; China University of Chinese Academy of Sciences, Beijing, 100049, China; School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai, 201203, China; Corresponding author. Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Wei Guo
Institute of Cancer Stem Cells, Dalian Medical University, Dalian, 116044, China; Corresponding author. Dalian Medical University, Dalian, China.
As the largest subunit of the nuclear remodeling factor complex, Bromodomain PHD Finger Transcription Factor (BPTF) has been reported to be involved in tumorigenesis and development in several cancers. However, to date, its functions and related molecular mechanisms in colorectal cancer (CRC) are still poorly defined and deserve to be revealed. In this study, we uncovered that, under the expression regulation of c-Myc, BPTF promoted CRC progression by targeting Cdc25A. BPTF was found to be highly expressed in CRC and promoted the proliferation and metastasis of CRC cells through BPTF specific siRNAs, shRNAs or inhibitors. Based on RNA-seq, combined with DNA-pulldown, ChIP and luciferase reporter assay, we proved that, by binding to −178/+107 region within Cdc25A promoter, BPTF transcriptionally activated Cdc25A, thus accelerating the cell cycle process of CRC cells. Meanwhile, BPTF itself was found to be transcriptionally regulated by c-Myc. Moreover, BPTF knockdown or inactivation was verified to sensitize CRC cells to chemotherapeutics, 5-Fluorouracil (5FU) and Oxaliplatin (Oxa), c-Myc inhibitor and cell cycle inhibitor not just at the cellular level in vitro, but in subcutaneous xenografts or AOM/DSS-induced in situ models of CRC in mice, while Cdc25A overexpression partially reversed BPTF silencing-caused tumor growth inhibition. Clinically, BPTF, c-Myc and Cdc25A were highly expressed in CRC tissues simultaneously, the expression of any two of the three was positively correlated, and their expressions were highly relevant to tumor differentiation, TNM staging and poor prognosis of CRC patients. Thus, our study indicated that the targeted inhibition of BPTF alone, or together with chemotherapy and/or cell cycle-targeted therapy, might act as a promising new strategy for CRC treatment, while c-Myc/BPTF/Cdc25A signaling axis is expected to be developed as an associated set of candidate biomarkers for CRC diagnosis and prognosis prediction.
