title: MYC regulation of CHK1 and CHK2 promotes radioresistance in a stem cell-like population of nasopharyngeal carcinoma cells.
abstract: Radiotherapy is the most successful nonsurgical treatment for nasopharyngeal carcinoma (NPC). Despite this, the prognosis remains poor. Although NPCs initially respond well to a full course of radiation, recurrence is frequent. The cancer stem cell (CSC) hypothesis provides a framework for explaining the discrepancy between the response of NPC to therapy and the poor survival rate. In this study, a stem cell-like subpopulation (PKH26+) was identified in NPC cell lines using a label-retention technique. PKH26+ cells were enriched for clonogenicity, sphere formation, side-population cells, and resistance to radiotherapy. Using genomic approaches, we show that the proto-oncogene c-MYC (MYC) regulates radiotolerance through transcriptional activation of CHK1 (CHEK1) and CHK2 (CHEK2) checkpoint kinases through direct binding to the CHK1 and CHK2 promoters. Overexpression of c-MYC in the PKH26+ subpopulation leads to increased expression of CHK1 and CHK2 and subsequent activation of the DNA-damage-checkpoint response, resulting in radioresistance. Furthermore, loss of CHK1 and CHK2 expression reverses radioresistance in PKH26+ (c-MYC high expression) cells in vitro and in vivo. This study elucidates the role of the c-MYC-CHK1/CHK2 axis in regulating DNA-damage-checkpoint responses and stem cell characteristics in the PKH26+ subpopulation. Furthermore, these data reveal a potential therapeutic application in reversal of radioresistance through inhibition of the c-MYC-CHK1/CHK2 pathway.
authors.affiliation: Cancer Research Institute of Southern Medical University, Guangzhou, China.
authors.forename: Wen-Jun
authors.initials: WJ
authors.lastname: Wang
authors.forename: Si-Pei
authors.initials: SP
authors.lastname: Wu
authors.forename: Jia-Bin
authors.initials: JB
authors.lastname: Liu
authors.forename: Yong-Sheng
authors.initials: YS
authors.lastname: Shi
authors.forename: Xue
authors.initials: X
authors.lastname: Huang
authors.forename: Qian-Bing
authors.initials: QB
authors.lastname: Zhang
authors.forename: Kai-Tai
authors.initials: KT
authors.lastname: Yao
mesh_terms: D000818:Animals; D002277:Carcinoma; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D064447:Checkpoint Kinase 2; D004249:DNA Damage; D004260:DNA Repair; D005260:Female; D006801:Humans; D051379:Mice; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D014411:Neoplastic Stem Cells / Q000528:radiation effects*; D009930:Organic Chemicals / Q000032:analysis; D011494:Protein Kinases / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D011836:Radiation Tolerance
chemical_list: C000715470:MAS1 protein, human; C489427:MYC protein, human; D009930:Organic Chemicals; C070080:PKH 26; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C000605867:CHEK1 protein, human; C578634:CHEK2 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse; C578633:Chek2 protein, mouse; D017346:Protein Serine-Threonine Kinases