title: G9a governs colon cancer stem cell phenotype and chemoradioresistance through PP2A-RPA axis-mediated DNA damage response.
abstract: Neoadjuvant concurrent chemoradiotherapy (CCRT) is a standard treatment of locally advanced colon cancer cell (CRC). In order to maximize efficacy and minimize toxicity, new drugs have been developed and used in combination with CCRT. Recently, it has been shown that G9a plays a role in mediating phenotypes of cancer stem cells (CSCs). This study aimed to characterize G9a as a biomarker in predicting therapy response to prevent overtreatment and adverse effects in CRC patients.
  
  
  
  The primary tumors from 39 patients who received CCRT for rectal cancer were selected. In vivo tumor xenograft models for tumorigenic properties in immunodeficient mice were developed. In vitro stemness ability was performed by tumor-sphere assays, cell response to anti-cancer agents and stemness-related genes analysis.
  
  
  
  Cells survived from radiation treatment, and displayed high levels of G9a. A significantly positive correlation was shown between G9a and CSCs marker CD133 in locally advanced rectal cancer patients with CCRT. Knockdown of G9a increased the sensitivity of cells to radiation treatment and sensitized cells to DNA damage agents through PP2A-RPA axis.
  
  
  
  Our study theorized that G9a might serve as a novel target in colon cancer, which offers exciting potential in prediction of response to preoperative chemoradiotherapy in patients with advanced CRC.
authors.affiliation: Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Taiwan.
authors.forename: Chi-Wen
authors.initials: CW
authors.lastname: Luo
authors.affiliation: Division of Colorectal Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Taiwan; Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Taiwan; Center for Biomarkers and Biotech Drugs, Kaohsiung Medical University, Taiwan; Research Center for Environmental Medicine, Kaohsiung Medical University, Taiwan.
authors.forename: Jaw-Yuan
authors.initials: JY
authors.lastname: Wang
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.
authors.forename: Wen-Chun
authors.initials: WC
authors.lastname: Hung
authors.affiliation: Department of Clinical Cancer Prevention, Unit 1013, The University of Texas MD Anderson Cancer Center, Houston, USA.
authors.forename: Guang
authors.initials: G
authors.lastname: Peng
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.
authors.forename: Ya-Li
authors.initials: YL
authors.lastname: Tsai
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.
authors.forename: Tsung-Ming
authors.initials: TM
authors.lastname: Chang
authors.affiliation: Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Taiwan.
authors.forename: Chee-Yin
authors.initials: CY
authors.lastname: Chai
authors.affiliation: Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Taiwan.
authors.forename: Chih-Hung
authors.initials: CH
authors.lastname: Lin
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Taiwan; Research Center for Environmental Medicine, Kaohsiung Medical University, Taiwan; Cancer Center, Kaohsiung Medical University Hospital, Taiwan. Electronic address: mrpan@cc.kmu.edu.tw.
authors.forename: Mei-Ren
authors.initials: MR
authors.lastname: Pan
mesh_terms: D000071916:AC133 Antigen / Q000378:metabolism; D000818:Animals; D059248:Chemoradiotherapy; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000628:therapy*; D004249:DNA Damage; D019008:Drug Resistance, Neoplasm; D045325:HCT116 Cells; D019073:HT29 Cells; D006649:Histocompatibility Antigens / Q000378:metabolism*; D011495:Histone-Lysine N-Methyltransferase / Q000172:deficiency / Q000378:metabolism*; D006801:Humans; D043564:Inorganic Pyrophosphatase / Q000096:biosynthesis*; D008297:Male; D051379:Mice; D024101:Mitochondrial Proteins / Q000096:biosynthesis*; D020360:Neoadjuvant Therapy; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects*; D010641:Phenotype; D011836:Radiation Tolerance; D051716:Replication Protein A / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000071916:AC133 Antigen; D006649:Histocompatibility Antigens; D024101:Mitochondrial Proteins; C000606023:PROM1 protein, human; D051716:Replication Protein A; C445405:EHMT2 protein, human; D011495:Histone-Lysine N-Methyltransferase; D043564:Inorganic Pyrophosphatase; C509848:PPA2 protein, human
keywords: CD133; Cancer stem cells; Chemoradioresistance; DNA damage response; G9a; PP2A