DNA methyltransferase 1 is essential for initiation of the colon cancers

• DOI: 10.1016/j.yexmp.2012.10.004
• Publication Date: 2012-10-09T06:17:29Z
• Authors: Rena Morita; Yoshihiko Hirohashi; Hiromu Suzuki; Akari Takahashi; Yasuaki Tamura; Takayuki Kanaseki; Hiroko Asanuma; Satoko Inoda; Toru Kondo; Satoshi Hashino; Tadashi Hasegawa; Takashi Tokino; Minoru Toyota; Masahiro Asaka; Toshihiko Torigoe; Noriyuki Sato
• Keywords: DNA (Cytosine-5-)-Methyltransferase 1; 0301 basic medicine; CD24 Antigen; Mice, SCID; HCT116 Cells; Xenograft Model Antitumor Assays; 3. Good health; Mice; 03 medical and health sciences; Cell Transformation, Neoplastic; Hyaluronan Receptors; Mice, Inbred NOD; Gene Knockdown Techniques; Colonic Neoplasms; Neoplastic Stem Cells; Animals; Humans; RNA Interference; DNA (Cytosine-5-)-Methyltransferases; RNA, Small Interfering; Neoplasm Transplantation

DNA methyltransferase 1 (Dnmt1) is essential for the maintenance of hematopoietic and somatic stem cells in mice; however, its roles in human cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) are still elusive. In the present study, we investigated DNMT1 functions in the maintenance of human colon CSCs/CICs using the human colon cancer cell line HCT116 (HCT116 w/t) and its DNMT1 knockout cell line (DNMT1(-/-)). The rates of CSCs/CICs were evaluated by side population (SP) analysis, ALDEFLUOR assay and expression of CD44 and CD24. SP, ALDEFLUOR-positive (ALDEFLUOR(+)) and CD44-positive and CD24-positive (CD44(+)CD24(+)) cell rates were lower in DNMT1(-/-) cells than in HCT116 w/t cells. Since CSCs/CICs have higher tumor-initiating ability than that of non-CSCs/CICs, the tumor-initiating abilities were addressed by injecting immune deficient (NOD/SCID) mice. DNMT1(-/-) cells showed less tumor-initiating ability than did HCT116 w/t cells, whereas the growing rate of DNMT1(-/-) cells showed no significant difference from that of HCT116 cells both in vitro and in vivo. Similar results were obtained for cells in which DNMT1 had been transiently knocked-down using gene-specific siRNAs. Taken together, these results indicate that DNMT1 is essential for maintenance of colon CSCs/CICs and that short-term suppression of DNMT1 might be sufficient to disrupt CSCs/CICs.