Journal
CANCER LETTERS
Volume 415, Issue -, Pages 58-72Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2017.11.040
Keywords
Colorectal cancer (CRC); Oxaliplatin resistance; E2F1; NFYB; CHK1
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Funding
- Zhejiang Medical and Health Science and Technology Plan [2018KY920, 2018KY184, 2016KYB330, 2017KY722]
- Taizhou Science and Technology Plan [1601KY61]
- National Natural Science Foundation of China [81702401]
- Zhejiang Provincial Natural Science Foundation of China [LQ16H160014]
- Science and Technology Program of Sanmen County Public Technology Social Development Project [16312]
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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 K, 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. (C) 2017 Elsevier B.V. All rights reserved.
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