Yongwei Lai1,2, Zhao He1, Aowei Zhang1, Zhinan Yan1, Xiao Zhang1, Shiyue Hu1, Nan Wang1, Hongpeng He3. 1. Key Laboratory of Industrial Microbiology, Ministry of Education and Tianjin City State Key Laboratory of Food Nutrition and Safety College of Biotechnology, Tianjin University of Science and Technology, No. 29, 13th. Avenue, Tianjin Economic and Technological Development Area (TEDA), Tianjin, 300457, People's Republic of China. 2. Department of Pharmacology, Jilin Medical University, Jilin City, 132013, Jilin Province, People's Republic of China. 3. Key Laboratory of Industrial Microbiology, Ministry of Education and Tianjin City State Key Laboratory of Food Nutrition and Safety College of Biotechnology, Tianjin University of Science and Technology, No. 29, 13th. Avenue, Tianjin Economic and Technological Development Area (TEDA), Tianjin, 300457, People's Republic of China. hehongpeng@tust.edu.cn.
Abstract
BACKGROUND: High-risk HPV is a causative factor of cervical cancer. HPV DNA fragments integrate into host genome resulting in the constitutive expression of HPV genes E6 and E7 under the regulation of transcription factors, such as p300 and Tip60. Interestingly, Tip60, a factor with HAT (histone acetyl transferase) activity, represses HPV18 E6/E7 genes while another HAT p300 activates the transcription of HPV18 E6/E7. OBJECTIVE: To explore the mechanism for the opposite roles of Tip60 and p300 in the virus gene regulation, and the influence of Tip60 and p300 in histone modifications in the regulatory sequence of HPV18 genes. METHODS: Tip60 or p300 was either knocked down or overexpressed in HeLa cells. The effects on HPV E6E7 expression were determined with RT-qPCR. The association of RNA polymerase II and the enrichment of acetylated or methylated histones in HPV promoter region were measured by ChIP assays with specific antibodies. RESULTS: ChIP results showed that Tip60 and p300 differently affected the modifications of histone H3K9 and the deposition of nucleosomes in HPV18 long control region (LCR). HPV18 LCR in HeLa cells is bivalent chromatin carrying both the active histone H3K9 acetylation mark and the repressive histone H3K9 trimethylation mark, the balance is maintained by Tip60 and p300. CONCLUSION(S): Based on the roles of Tip60 and p300 in HPV gene regulation, chemical compounds targeting Tip60 or p300 are potential anti-cervical cancer drugs.
BACKGROUND: High-risk HPV is a causative factor of cervical cancer. HPV DNA fragments integrate into host genome resulting in the constitutive expression of HPV genes E6 and E7 under the regulation of transcription factors, such as p300 and Tip60. Interestingly, Tip60, a factor with HAT (histone acetyl transferase) activity, represses HPV18 E6/E7 genes while another HAT p300 activates the transcription of HPV18 E6/E7. OBJECTIVE: To explore the mechanism for the opposite roles of Tip60 and p300 in the virus gene regulation, and the influence of Tip60 and p300 in histone modifications in the regulatory sequence of HPV18 genes. METHODS:Tip60 or p300 was either knocked down or overexpressed in HeLa cells. The effects on HPV E6E7 expression were determined with RT-qPCR. The association of RNA polymerase II and the enrichment of acetylated or methylated histones in HPV promoter region were measured by ChIP assays with specific antibodies. RESULTS: ChIP results showed that Tip60 and p300 differently affected the modifications of histone H3K9 and the deposition of nucleosomes in HPV18 long control region (LCR). HPV18 LCR in HeLa cells is bivalent chromatin carrying both the active histone H3K9 acetylation mark and the repressive histone H3K9 trimethylation mark, the balance is maintained by Tip60 and p300. CONCLUSION(S): Based on the roles of Tip60 and p300 in HPV gene regulation, chemical compounds targeting Tip60 or p300 are potential anti-cervical cancer drugs.