XPC deficiency leads to centrosome amplification by inhibiting BRCA1 expression upon cisplatin-mediated DNA damage in human bladder cancer. (1st March 2019)

• Record Type: Journal Article
• Authors: Wang, Huanhuan; Huang, Yaqin; Shi, Jiazhong; Zhi, Yi; Yuan, Fang; Yu, Jin; Chen, Zhiwen; Yang, Jin
• Is Part Of: Cancer letters. Volume 444(2019)
• Page Start: 136
• Page End: 146
• Publication Date: 2019-03-01
• Subjects: XPC -- Centrosome amplification -- DNA damage response -- Bladder cancer; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2018.12.004
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: Xeroderma pigmentosum group C (XPC) is a well-known DNA damage recognition protein. Defects in XPC lead to carcinogenesis and progression of many human cancers. In the current study, we defined a novel, important role of XPC in preventing centrosome amplification during cisplatin-mediated DNA damage response. From experiments with human bladder cancer tissue, urothelial tissue from Xpc knockout mice and XPC-silenced cell lines, we found that attenuated XPC expression was associated with increased centrosome amplification in human bladder cancer. A significant increase in centrosome amplification was observed in XPC-silenced cells upon cisplatin treatment. XPC deficiency leads to reduced BRCA1 expression via upregulating its transcriptional repressor, Pit-1. The BRCA1 downregulation results in more DNA double strand breaks accumulation and persistent activation of the ATM-Chk1/Chk2 signaling, resulting in a prolonged G2/M arrest during which centrosome can over-duplicate and lead to centrosome amplification. XPC complementation in silenced cells could reduce Pit-1 expression, increase BRCA1 expression and recover the status of centrosome amplification. Our study reveals a new function for XPC in preventing chromosomal instability, providing new information on cancer chemotherapy and potential clinical significance for cancer management. Highlights: XPC deficiency leads to centrosome amplification in human bladder cancer. XPC deficiency increases Pit-1 expression which transcriptionally represses BRCA1. XPC deficiency reduces BRCA1 expression and accumulates more DNA double strand break. Persistent activation of ATM-Chk1/Chk2 signaling leads to prolonged G2/M arrest.