Loss of insulin-like growth factor II imprinting is a hallmark associated with enhanced chemo/radiotherapy resistance in cancer stem cells.
Insulin-like growth factor II (IGF2) is maternally imprinted in most tissues, but the epigenetic regulation of the gene in cancer stem cells (CSCs) has not been defined. To study the epigenetic mechanisms underlying self-renewal, we isolated CSCs and non-CSCs from colon cancer (HT29, HRT18, HCT116), hepatoma (Hep3B), breast cancer (MCF7) and prostate cancer (ASPC) cell lines. In HT29 and HRT18 cells that show loss of IGF2 imprinting (LOI), IGF2 was biallelically expressed in the isolated CSCs. Surprisingly, we also found loss of IGF2 imprinting in CSCs derived from cell lines HCT116 and ASPC that overall demonstrate maintenance of IGF2 imprinting. Using chromatin conformation capture (3C), we found that intrachromosomal looping between the IGF2 promoters and the imprinting control region (ICR) was abrogated in CSCs, in parallel with loss of IGF2 imprinting in these CSCs. Loss of imprinting led to increased IGF2 expression in CSCs, which have a higher rate of colony formation and greater resistance to chemotherapy and radiotherapy in vitro. These studies demonstrate that IGF2 LOI is a common feature in CSCs, even when the stem cells are derived from a cell line in which the general population of cells maintain IGF2 imprinting. This finding suggests that aberrant IGF2 imprinting may be an intrinsic epigenetic control mechanism that enhances stemness, self-renewal and chemo/radiotherapy resistance in cancer stem cells.
Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130021, China.
Xin
X
Zhao
Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130021, China.
Xiaoliang
X
Liu
Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130021, China.
Guanjun
G
Wang
Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130021, China.
Xue
X
Wen
Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130021, China.
Xiaoying
X
Zhang
Stanford University Medical School, Palo Alto Veterans Institute for Research, Palo Alto, CA 94304, USA.
Andrew R
AR
Hoffman
Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130021, China.
Wei
W
Li
Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130021, China.|Stanford University Medical School, Palo Alto Veterans Institute for Research, Palo Alto, CA 94304, USA.
Ji-Fan
JF
Hu
Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130021, China.
Jiuwei
J
Cui
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018392:Genomic Imprinting; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics*; D061986:MCF-7 Cells; D008297:Male; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D011401:Promoter Regions, Genetic; D011836:Radiation Tolerance / Q000235:genetics*
D014408:Biomarkers, Tumor; C035170:IGF2 protein, human; D007335:Insulin-Like Growth Factor II
IGF2; cancer stem cells; epigenetics; genomic imprinting; intrachromosomal looping