Abstract 4297: MYC HIF-2 alpha embryonic stemness genes mediate a transcriptional network to maintain asymmetric self-renewal in oral cancer

Abstract

Abstract Cancer Stem Cells (CSCs) explains therapeutic failure across several tumor types. Despite being evolutionarily successful, the extreme ability to self-renew is asymmetric and limited to CSCs in heterogeneous tumor population. Thus, understanding molecular mechanisms maintaining CSCs asymmetric self-renewal would be therapeutically critical.Here, we identified putative molecular transcriptional network that may regulate CSCs asymmetric self-renewal. We developed 4-NQO (4-Nitroquinoline 1-oxide) induced mouse model of oral carcinogenesis that exhibited similar phenotype as human oral cancer. ABCG2+ CSCs enriched from 4-NQO derived mouse tumors and human oral cancer (n=7) patients indicated high expression of embryonic stemness genes such as Nanog, Sox-2, and Oct-4 in addition to MYC and HIF-2a. Higher engraftment potential was observed when ABCG2+ cells were injected to NOD/SCID mice, while HIF-2a silencing markedly increased mice survival during engraftments. ChIP assay revealed preferential binding of MYC to HIF-2a promoter regions in ABCG2+ vs ABCG2- cells. Nanog and Oct4 facilitated MYC binding to HIF-2a while gene silencing of Nanog and Sox2 led to loss of MYC and HIF-2a expression, indicating the possible regulation by MYC and HIF-2a. Further, we utilized clinical data from The Cancer Genome Atlas (TCGA) and demonstrated significant correlation between HIF-2a/MYC and embryonic stemness genes on Structural Equation Modeling Analysis (SEMA) platform, thereby confirming our in vitro/in vivofindings. Thus,our results may provide evidence of a biologically robust stemness transcriptional network regulating the asymmetric self-renewal of ABCG2+ CSCs. Note: This abstract was not presented at the meeting. Citation Format: Bidisha Pal, Wael Tasabehji, Sandhya Sorra, Joyeeta Talukdar, Bikul Das. MYC HIF-2 alpha embryonic stemness genes mediate a transcriptional network to maintain asymmetric self-renewal in oral cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4297.