Orphan nuclear receptor HNF4G promotes bladder cancer growth and invasion through the regulation of the hyaluronan synthase 2 gene

• Published in: Oncogenesis (New York, NY) Vol. 2; no. 7; p. e58
• Main Authors: Okegawa, T, Ushio, K, Imai, M, Morimoto, M, Hara, T
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 29-07-2013; Nature Publishing Group
• Subjects: 631/208/200; 631/67/322; 631/67/589/1336; 631/80/86/388; Apoptosis; Cell Biology; Human Genetics; Internal Medicine; Medicine; Medicine & Public Health; Oncology; Original; original-article; HNF4G; HAS2; growth; invasion; orphan nuclear receptor; bladder cancer
• ISSN: 2157-9024; 2157-9024
• DOI: 10.1038/oncsis.2013.25

Nuclear receptors (NRs) are a class of transcription factors that are closely involved in the progression of certain types of cancer. We aimed to study the relation between bladder cancer and NRs, with special focus on orphan NRs whose ligands and functions have not been identified. First, we examined the expression levels of 22 genes encoding orphan NRs in clinical bladder cancer and found that hepatocyte nuclear factor 4γ (
HNF4G
;
NR2A2
) and
NR2F6
were the genes that were upregulated most frequently in cancer tissues compared with their paired normal tissues. Knockdown and overexpression of each of these orphan NRs suppressed and stimulated the growth of bladder cancer cells
in vitro
, respectively. HNF4G also promoted tumor growth in bladder cancer xenograft models
in vivo
. Furthermore, HNF4G was both necessary and sufficient for the invasion of bladder cancer cells
in vitro
. Moreover, using microarray analyses, we identified
hyaluronan synthase 2
(
HAS2
) as one of the genes induced by HNF4G in bladder cancer cells. Transcription was activated by HNF4G in reporter assays using the promoter/enhancer region of the
HAS2
gene. The endogenous expression of the
HAS2
gene was suppressed by knockdown of HNF4G. In turn, knockdown of HAS2 inhibited the growth and invasion of bladder cancer cells. Taken together, our data suggest that some orphan NRs are involved in bladder cancer progression and that, among them, HNF4G promotes the growth and invasion of bladder cancer, at least in part, via the regulation of the
HAS2
gene.