PEG10 is a c-MYC target gene in cancer cells.
The product of the imprinted gene paternally expressed gene-10 (PEG10) has been reported to support proliferation in hepatocellular carcinomas, but how this gene is regulated has been an open question. We find that MYC knockdown by RNA interference suppresses PEG10 expression in Panc1 pancreatic carcinoma and HepG2 hepatocellular carcinoma cells and that knockdown of PEG10 inhibits the proliferation of Panc1, HepG2, and Hep3B cells. Conversely, PEG10 was up-regulated by inducing c-MYC expression in a B-lymphocyte cell line. Chromatin immunoprecipitation from Panc1 cells showed c-MYC bound to an E-box-containing region in the PEG10 first intron and site-directed mutagenesis showed that the most proximal E-box is essential for promoter activity. In a mouse mammary tumor virus (MMTV)-MYC transgenic mouse model of breast cancer, most but not all of the mammary carcinomas had strongly increased Peg10 mRNA compared with normal mammary gland. By immunohistochemistry, normal human breast and prostate epithelium was negative for the major isoform [reading frame-1 (RF1)] of PEG10 protein, but this cytoplasmic protein was strongly expressed in a subset of breast carcinomas in situ and invasive ductal carcinomas ( approximately 30%) and in a similar percentage of prostate cancers. As in the mouse model, we found positive, but not absolute, correlations between PEG10 and c-MYC in tissue arrays containing 161 human breast cancers (P < 0.002) and 30 prostate cancers (P = 0.014). Immunostaining of human placenta showed PEG10 and c-MYC proteins coexpressed in proliferating cytotrophoblast and coordinately lost in postmitotic syncytiotrophoblast. These findings link cancer genetics and epigenetics by showing that a classic proto-oncogene, MYC, acts directly upstream of a proliferation-positive imprinted gene, PEG10.
Li
Chi-Ming
CM
Institute for Cancer Genetics, Columbia University Medical Center, 1150 St. Nicholas Avenue, New York, NY 10032, USA.
Margolin
Adam A
AA
Salas
Martha
M
Memeo
Lorenzo
L
Mansukhani
Mahesh
M
Hibshoosh
Hanina
H
Szabolcs
Matthias
M
Klinakis
Apostolos
A
Tycko
Benjamin
B
D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation; D004268:DNA-Binding Proteins; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology; D015674:Mammary Neoplasms, Animal / Q000235:genetics / Q000821:virology; D051379:Mice; D008822:Mice, Transgenic; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000473:pathology; D011506:Proteins / Q000235:genetics* / Q000502:physiology*; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000502:physiology*; D034622:RNA Interference; D016601:RNA-Binding Proteins; D014407:Tumor Cells, Cultured
D051017:Apoptosis Regulatory Proteins; D004268:DNA-Binding Proteins; C000715470:MAS1 protein, human; C489427:MYC protein, human; C432965:PEG10 protein, human; D011506:Proteins; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc; D016601:RNA-Binding Proteins