Zebularine inhibits tumorigenesis and stemness of colorectal cancer via p53-dependent endoplasmic reticulum stress.
Aberrant DNA hypermethylation is frequently found in tumor cells and inhibition of DNA methylation is an effective anticancer strategy. In this study, the therapeutic effect of DNA methyltransferase (DNMT) inhibitor zebularine (Zeb) on colorectal cancer (CRC) was investigated. Zeb exhibited anticancer activity in cell cultures, tumor xenografts and mouse colitis-associated CRC model. It stabilizes p53 through ribosomal protein S7 (RPS7)/MDM2 pathways and DNA damage. Zeb-induced cell death was dependent on p53. Microarray analysis revealed that genes related to endoplasmic reticulum (ER) stress and unfolded protein response (UPR) were affected by Zeb. Zeb induced p53-dependent ER stress and autophagy. Pro-survival markers of ER stress/UPR (GRP78) and autophagy (p62) were increased in tumor tissues of CRC patients, AOM/DSS-induced CRC mice and HCT116-derived colonospheres. Zeb downregulates GRP78 and p62, and upregulates a pro-apoptotic CHOP. Our results reveal a novel mechanism for the anticancer activity of Zeb.
1] Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan [2] The Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan [3].
Pei-Ming
PM
Yang
Yi-Ting
YT
Lin
Chia-Tung
CT
Shun
Shan-Hu
SH
Lin
Tzu-Tang
TT
Wei
Shu-Hui
SH
Chuang
Ming-Shiang
MS
Wu
Ching-Chow
CC
Chen
D000818:Animals; D001343:Autophagy / Q000187:drug effects; D063646:Carcinogenesis / Q000187:drug effects* / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D003562:Cytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects; D019175:DNA Methylation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D012269:Ribosomal Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D056811:Unfolded Protein Response / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; D012269:Ribosomal Proteins; D016159:Tumor Suppressor Protein p53; C037442:ribosomal protein S7; D003562:Cytidine; C009131:pyrimidin-2-one beta-ribofuranoside; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2