HNF4α orchestrates a set of 14 genes to down-regulate cell proliferation in kidney cells

Abstract

Abstract Few genes are known to be involved in renal cell carcinoma (RCC) development and progression. The cell-specific transcription factor hepatocyte nuclear factor 4α (HNF4α) is down-regulated in RCC and we have shown that HNF4α inhibits cell proliferation in the embryonic kidney cell line HEK293. To clarify the possible tumor suppressor activity of HNF4α we analyzed the whole human expression profile in HEK293 cells upon HNF4α induction. By comparing induced and uninduced cells, we identified 1411 differentially expressed genes. Using RNA interference, we screened 56 HNF4α-regulated genes for their possible role in mediating inhibition of cell proliferation triggered by HNF4α. We demonstrate that 14 of these regulated genes are able to contribute to the inhibitory effect of HNF4α on cell proliferation, including well-known cancer genes, such as CDKN1A (p21), TGFA, MME (NEP) and ADAMTS1. In addition, the genes SEPP1, THEM2, BPHL, DSC2, ANK3, ALDH6A1, EPHX2, NELL2, EFHD1 and PROS1 are also part of the network of HNF4α target genes that regulate proliferation in HEK293 cells. Therefore, we postulate that HNF4α orchestrates, at least, these 14 genes to regulate cell proliferation in HEK293 cells and that down-regulation of HNF4α could contribute to the progression of kidney cancer.