Identification and functional analysis of 9p24 amplified genes in human breast cancer
Previously, our group identified a novel amplicon at chromosome 9p24 in human esophageal and breast cancers, and cloned the novel gene, GASC1 ( gene amplified in squamous cell carcinoma 1 , also known as JMJD2C / KDM4C ), from this amplicon. GASC1 is a histone demethylase involved in the deregulatio...
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Veröffentlicht in: | Oncogene 2012-01, Vol.31 (3), p.333-341 |
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Zusammenfassung: | Previously, our group identified a novel amplicon at chromosome 9p24 in human esophageal and breast cancers, and cloned the novel gene,
GASC1
(
gene amplified in squamous cell carcinoma 1
, also known as
JMJD2C
/
KDM4C
), from this amplicon. GASC1 is a histone demethylase involved in the deregulation of histone methylation in cancer cells. In the current study, we aimed to comprehensively characterize the genes in the 9p24 amplicon in human breast cancer. We performed extensive genomic analyses on a panel of cancer cell lines and narrowed the shortest region of overlap to approximately 2 Mb. Based on statistical analysis of copy number increase and overexpression, the 9p24 amplicon contains six candidate oncogenes. Among these, four genes (
GASC1 UHRF2
,
KIAA1432
and
C9orf123
) are overexpressed only in the context of gene amplification while two genes (
ERMP1
and
IL33
) are overexpressed independent of the copy number increase. We then focused our studies on the
UHRF2
gene, which has a potential involvement in both DNA methylation and histone modification. Knocking down UHRF2 expression inhibited the growth of breast cancer cells specifically with 9p24 amplification. Conversely, ectopic overexpression of UHRF2 in non-tumorigenic MCF10A cells promoted cell proliferation. Furthermore, we demonstrated that UHRF2 has the ability to suppress the expression of key cell-cycle inhibitors, such as p16
INK4a
, p21
Waf1/Cip1
and p27
Kip1
. Taken together, our studies support the notion that the 9p24 amplicon contains multiple oncogenes that may integrate genetic and epigenetic codes and have important roles in human tumorigenesis. |
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ISSN: | 0950-9232 1476-5594 |
DOI: | 10.1038/onc.2011.227 |