Genomic amplification and oncogenic properties of the GASC1 histone demethylase gene in breast cancer.
Earlier, mapping of the 9p23-24 amplicon in esophageal cancer cell lines led us to the positional cloning of gene amplified in squamous cell carcinoma 1 (GASC1), which encodes a nuclear protein with a Jumonji C domain that catalyzes lysine (K) demethylation of histones. However, the transforming roles of GASC1 in breast cancer remain to be determined. In this study, we identified GASC1 as one of the amplified genes for the 9p23-24 region in breast cancer, particularly in basal-like subtypes. The levels of GASC1 transcript expression were significantly higher in aggressive, basal-like breast cancers compared with nonbasal-like breast cancers. Our in vitro assays demonstrated that GASC1 induces transformed phenotypes, including growth factor-independent proliferation, anchorage-independent growth, altered morphogenesis in Matrigel, and mammosphere forming ability, when overexpressed in immortalized, nontransformed mammary epithelial MCF10A cells. Additionally, GASC1 demethylase activity regulates the expression of genes critical for stem cell self-renewal, including NOTCH1, and may be linked to the stem cell phenotypes in breast cancer. Thus, GASC1 is a driving oncogene in the 9p23-24 amplicon in human breast cancer and targeted inhibition of GASC1 histone demethylase in cancer could provide potential new avenues for therapeutic development.
Department of Pathology, Breast Cancer Program, Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA.
G
G
Liu
A
A
Bollig-Fischer
B
B
Kreike
M J
MJ
van de Vijver
J
J
Abrams
S P
SP
Ethier
Z-Q
ZQ
Yang
D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D002899:Chromosomes, Human, Pair 9; D005260:Female; D005784:Gene Amplification; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics*; D009857:Oncogenes; D012333:RNA, Messenger / Q000032:analysis; D051881:Receptor, Notch1 / Q000235:genetics
C413655:KDM4C protein, human; C497761:NOTCH1 protein, human; D012333:RNA, Messenger; D051881:Receptor, Notch1; D056484:Jumonji Domain-Containing Histone Demethylases