title: Lysine acetyltransferase GCN5 potentiates the growth of non-small cell lung cancer via promotion of E2F1, cyclin D1, and cyclin E1 expression.
abstract: The lysine acetyltransferases play crucial but complex roles in cancer development. GCN5 is a lysine acetyltransferase that generally regulates gene expression, but its role in cancer development remains largely unknown. In this study, we report that GCN5 is highly expressed in non-small cell lung cancer tissues and that its expression correlates with tumor size. We found that the expression of GCN5 promotes cell growth and the G1/S phase transition in multiple lung cancer cell lines. Further study revealed that GCN5 regulates the expression of E2F1, cyclin D1, and cyclin E1. Our reporter assays indicated that the expression of GCN5 enhances the activities of the E2F1, cyclin D1, and cyclin E1 promoters. ChIP experiments suggested that GCN5 binds directly to these promoters and increases the extent of histone acetylation within these regions. Mechanistic studies suggested that GCN5 interacts with E2F1 and is recruited by E2F1 to the E2F1, cyclin D1, and cyclin E1 promoters. The function of GCN5 in lung cancer cells is abrogated by the knockdown of E2F1. Finally, we confirmed that GCN5 regulates the expression of E2F1, cyclin D1, and cyclin E1 and potentiates lung cancer cell growth in a mouse tumor model. Taken together, our results demonstrate that GCN5 specifically potentiates lung cancer growth by directly promoting the expression of E2F1, cyclin D1, and cyclin E1 in an E2F1-dependent manner. Our study identifies a specific and novel function of GCN5 in lung cancer development and suggests that the GCN5-E2F1 interaction represents a potential target for lung cancer treatment.
authors.affiliation: Clinical and Translational Research Center of Shanghai First Maternity and Infant Health Hospital, Shanghai Key Laboratory of Signaling and Disease Research at School of Life Science and Technology, Tongji University, No. 1239 Si-ping Road, Shanghai 200092.
authors.forename: Long
authors.initials: L
authors.lastname: Chen
authors.affiliation: Clinical and Translational Research Center of Shanghai First Maternity and Infant Health Hospital, Shanghai Key Laboratory of Signaling and Disease Research at School of Life Science and Technology, Tongji University, No. 1239 Si-ping Road, Shanghai 200092.
authors.forename: Tingyi
authors.initials: T
authors.lastname: Wei
authors.affiliation: Clinical and Translational Research Center of Shanghai First Maternity and Infant Health Hospital, Shanghai Key Laboratory of Signaling and Disease Research at School of Life Science and Technology, Tongji University, No. 1239 Si-ping Road, Shanghai 200092.
authors.forename: Xiaoxing
authors.initials: X
authors.lastname: Si
authors.affiliation: Department of Hematology and Laboratory Medicine, Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai 200433, China.
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Clinical and Translational Research Center of Shanghai First Maternity and Infant Health Hospital, Shanghai Key Laboratory of Signaling and Disease Research at School of Life Science and Technology, Tongji University, No. 1239 Si-ping Road, Shanghai 200092.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Clinical and Translational Research Center of Shanghai First Maternity and Infant Health Hospital, Shanghai Key Laboratory of Signaling and Disease Research at School of Life Science and Technology, Tongji University, No. 1239 Si-ping Road, Shanghai 200092.
authors.forename: Ye
authors.initials: Y
authors.lastname: Leng
authors.affiliation: Department of Hematology and Laboratory Medicine, Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai 200433, China.
authors.forename: Anmei
authors.initials: A
authors.lastname: Deng
authors.affiliation: Department of Hematology and Laboratory Medicine, Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai 200433, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.affiliation: Clinical and Translational Research Center of Shanghai First Maternity and Infant Health Hospital, Shanghai Key Laboratory of Signaling and Disease Research at School of Life Science and Technology, Tongji University, No. 1239 Si-ping Road, Shanghai 200092.
authors.forename: Guiying
authors.initials: G
authors.lastname: Wang
authors.affiliation: Clinical and Translational Research Center of Shanghai First Maternity and Infant Health Hospital, Shanghai Key Laboratory of Signaling and Disease Research at School of Life Science and Technology, Tongji University, No. 1239 Si-ping Road, Shanghai 200092. Electronic address: zhusongcheng@tongji.edu.cn.
authors.forename: Songcheng
authors.initials: S
authors.lastname: Zhu
authors.affiliation: Clinical and Translational Research Center of Shanghai First Maternity and Infant Health Hospital, Shanghai Key Laboratory of Signaling and Disease Research at School of Life Science and Technology, Tongji University, No. 1239 Si-ping Road, Shanghai 200092. Electronic address: jhkang@tongji.edu.cn.
authors.forename: Jiuhong
authors.initials: J
authors.lastname: Kang
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000378:metabolism*; D019927:Cyclin E / Q000378:metabolism*; D050687:E2F1 Transcription Factor / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism*; D008239:Lysine / Q000737:chemistry; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D015513:Oncogene Proteins / Q000378:metabolism*; D050880:p300-CBP Transcription Factors / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
chemical_list: D019938:Cyclin D1; D019927:Cyclin E; D050687:E2F1 Transcription Factor; D008239:Lysine; D015513:Oncogene Proteins; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C530104:CCND1 protein, human; C475820:CCNE1 protein, human
keywords: Cancer Prevention; Cancer biology; Cell Cycle; E2F1; GCN5; Gene Regulation; Histone Acetylase; Lung Cancer; Lysine Acetyltransferase (KAT)
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