Human ZNF312b Promotes the Progression of Gastric Cancer by Transcriptional Activation of the K-ras Gene

Abstract

Gastric cancer ranks second among the most common causes of cancer deaths worldwide. Recent studies reported target molecules that are candidates for new therapeutic interventions; however, their molecular mechanism has not been clearly defined. In this study, we found that ZNF312b plays a role in tumor progression and metastasis in gastric cancer via transcriptional activation of the K-ras oncogene. ZNF312b seems to be specifically overexpressed in gastric cancer tissues and cell lines. The overexpression of ZNF312b induces cancerlike phenotypes, including accelerated proliferation and increased tumor masses in nude mice, which are completely reversed by its knockdown in gastric cancer cell lines, implying direct involvement in gastric tumor progression. From analyses using deletion mutants of ZNF312b and K-ras promoter-driven luciferase reporters, we found that it translocates into the nucleus via the proline-rich domain of its COOH terminus to activate transcription of the K-ras gene, resulting in an enhancement of the extracellular signalregulated kinase signaling pathway that governs cell proliferation. Taken together, these results suggest that ZNF312b contributes to the promotion of gastric cancer by triggering K-ras oncogene expression. The current study is the first to report that ZNF312b, a novel transcription factor, was associated with tumorigenicity of gastric cancer. This might be a valuable target that could provide new insight into the development of new therapeutic modalities for patients with gastric cancer. [Cancer Res 2009;69(7):3131-9]

Human ZNF312b oncogene is regulated by Sp1 binding to its promoter region through DNA demethylation and histone acetylation in gastric cancer

“…Real-time polymerase chain reaction (qPCR) was performed as described in a previous report. 6 The primers for qPCR were designed and summarized in Supporting Information Table 1.…”

“…6 Such distinct expression patterns of the ZNF312b gene in specific gastric cancer cell types provided an appropriate setting for the investigation of epigenetic features associated with the state of ZNF312b expression. The ZNF312b gene 5 0 -flanking region (2 kb) was analyzed using the CpG plot program (http:// www.ebi.ac.uk/Tools/emboss/cpgplot/).…”

“…[1][2][3][4][5] Through function studies of these candidate genes, in vitro and/or in vivo, a few have been reported as target genes associated with tumorigenicity of gastric cancer. 2,3,[6][7][8][9] CDC20 has recently been seen as a biological mechanism that is negatively regulated in a p53-dependent manner through CDE-CHR elements of the CDC20 promoter. 7 The protein arginine methyltransferase 5, which mediates the transfer of methyl groups to arginines in proteins involved in signal transduction, also is known as a major pro-survival factor regulating eIF4E expression and p53 translation.…”

“…8 In addition, the human ZNF312b gene has recently been known as a cancer-related gene that is highly expressed in gastric cancer cells. 2,6 ZNF312b is a zinc-finger gene that was originally isolated as a forebrain-and OSN-specific gene in Xenopus.…”

“…11 Recently, we reported that human ZNF312b makes a contribution to gastric tumor development. 6 In that report, ZNF312b was translocated into the nucleus via the proline-rich domain of its COOH terminus to activate transcription of the K-ras gene, regulating an enhancement of the extracellular signal regulated kinase (ERK) signaling pathway that governs cell proliferation. Thus, ZNF312b is a novel transcription factor associated with tumorigenicity of gastric cancer.…”