Abstract 4994: Downstream targets of Id1 transcription factor in non-small cell lung cancer

Abstract

Abstract Id1 (Inhibitor of DNA binding/Differentiation) is a helix loop helix (HLH) protein, regulates transcription by binding to bHLH transcription factors and preventing their binding to the DNA. Id1 is especially known to mediate repression of E box proteins and Ets transcription factors. Id1 gene is overexpressed in lung, breast, pancreatic and prostate cancer and it is thought to promote the progression and metastasis of these tumors. At the same time, not much is known about its role in non-small cell lung carcinoma.Preliminary studies from our lab shows that Nicotine as well as EGF induces Id1 in both adenocarcinoma and squamous carcinoma cells and is notably upregulated in metastatic lung cancers. Depletion of Id1 also prevents the proliferation and invasion of NSCLS cells. Attempts were made to understand the downstream effectors of Id1 function in lung cancer progression and metastasis. As a step in this direction, A549 (K-Ras mutant, EGFR wild-type) and H1650 (K-Ras wild-type, EGFR mutant) cells were transfected with short interfering RNA (siRNA) for Id1and stimulated with 1μm Nicotine or 100ng/ml EGF. The samples were subjected to microarray analysis to identify various genes upregulated and downregulated in the Id1 siRNA transfected cell lines. 200 genes were upregulated 2 fold or more by Nicotine and 150 by EGF. Few genes such as stathmin like-3 (STMN3), GSPT1 (G1 to S phase transition), TPD52 (tumor protein D52) were downregulated in the absence of Id1 suggesting those are Id1 regulated genes. The microarray results were validated using Real-time PCR for the above genes. Further depletion of these three genes resulted in decreased cell proliferation, migration and invasion. Indeed STMN3 promoter could be induced by Id1 and Id1 was necessary for Nicotine to induce this gene. These results might reveal the mechanisms by which Id1 promotes tumor progression and metastasis. STMN3 is a microtubule destabilizing phosphoprotein which is overexpressed in adenocarcinoma as well as squamous cell carcinoma and induced tumor cell proliferation, migration and matrix invasion in respective cell lines. GSPT1, which is also known as eukaryotic translation release factor eRF3 and TPD52 are also reported to be over expressed in various kinds of cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4994. doi:10.1158/1538-7445.AM2011-4994