NFYB-induced high expression of E2F1 contributes to oxaliplatin resistance in colorectal cancer via the enhancement of CHK1 signaling. (28th February 2018)

• Record Type: Journal Article
• Authors: Fang, Zejun; Gong, Chaoju; Yu, Songshan; Zhou, Weihua; Hassan, Waseem; Li, Hongzhang; Wang, Xue; Hu, Yanyan; Gu, Kaipeng; Chen, Xixi; Hong, Bing; Bao, Yuyan; Chen, Xiang; Zhang, Xiaomin; Liu, Hong
• Is Part Of: Cancer letters. Volume 415(2018)
• Page Start: 58
• Page End: 72
• Publication Date: 2018-02-28
• Subjects: Colorectal cancer (CRC) -- Oxaliplatin resistance -- E2F1 -- NFYB -- CHK1; CRC Colorectal cancer -- NFYB Nuclear transcription factor Y subunit beta -- E2F1 E2F transcription factor 1 -- CHK1 Checkpoint kinase 1 -- OR-CRC Oxaliplatin-resistant CRC -- DDR DNA damage response -- DEGs Differentially expressed genes -- OS Overall survival; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2017.11.040
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: As a third-generation platinum drug, oxaliplatin has been widely applied in colorectal cancer (CRC); however, acquired resistance to oxaliplatin has become a major obstacle. In the present study, we found that the nuclear transcription factor Y subunit beta (NFYB) and E2F transcription factor 1 (E2F1) expression levels were significantly higher in oxaliplatin-resistant DLD1 and RKO CRC (OR-CRC) cells than in non-resistant cells. Additionally, highly expressed NFYB transactivated the E2F1 gene, which is important to maintain oxaliplatin resistance in OR-CRC cells. And Sirt1-dependent deacetylation suppresses the proapoptotic activity of E2F1 in OR-CRC cells. Through profiling the transcriptome of OR-CRC cells following E2F1 knockdown, CHK1 was identified as a target of E2F1. Deprivation of CHK1 sensitized OR-CRC cells to oxaliplatin. In vitro and in vivo phenotype experiments confirmed that an intact NFYB-E2F1-CHK1 axis was required to suppress oxaliplatin-induced apoptosis and maintain the tumorigenicity in OR-CRC cells. Knockdown of E2F1 in OR-CRC cells also decreased the expression of Pol κ, which was essential for CHK1 activation. Consistently, a high level of NFYB, E2F1, or CHK1 predicted poor survival in CRC patients, especially with oxaliplatin treatment. Collectively, the NFYB-E2F1 pathway displays a crucial role in the chemoresistance of OR-CRC by inducing the expression and activation of CHK1, providing a possible therapeutic target for oxaliplatin resistance in CRC. Highlights: Overactivation of NFYB-E2F1-CHK1 in OR-CRC cells confers oxaliplatin-resistance. Highly expressed E2F1 increases Pol κ level and CHK1 activation in OR-CRC cells. Deacetylation of E2F1 by Sirt1 inhibits E2F1-induced apoptosis in OR-CRC cells. High level of NFYB, E2F1, or CHK1 indicates a poor survival in CRC patients.