Abstract 203: Hotair, a long non-coding RNA, exhibits pro-oncogenic activity in pancreatic cancer

Abstract

Abstract HOTAIR is a long intervening non-coding RNA (lincRNA) that represses specific gene transcription by interaction with the Polycomb Repressive Complex 2 (PRC2) that trimethylates histone H3 lysine 27, leading to reprograming of chromatin states. HOTAIR is a poor prognostic indicator for survival of breast, colon and liver cancer patients and is highly associated with cancer invasion and metastasis. In this study, we show that HOTAIR is more highly expressed in pancreatic tumors than normal tissue and is strongly correlated not only with cell invasiveness but also cell proliferation and death. Overexpression of HOTAIR increased cell invasion in pancreatic cancer cells expressing low levels of HOTAIR and this was previously observed in other cancer cell lines. However, unlike previous reports, HOTAIR knockdown in Panc1 and L3.6pL pancreatic cancer cells that overexpress this lincRNA decreased cell proliferation, altered cell cycle progression, and induced apoptosis, demonstrating an expanded function for HOTAIR in pancreatic cancer cells compared to other cancer cell lines. Results of gene profiling studies after HOTAIR knockdown showed that there was minimal overlap between HOTAIR-regulated genes in pancreatic vs. breast cancer cells and HOTAIR uniquely suppressed several interferon-related genes and genes related to cell cycle progression in pancreatic cancer cells. Consistently, Gene Set Enrichment Analysis (GSEA) shows that HOTAIR regulates gene sets relevant to cell proliferation using HOTAIR Knockdown gene profiling data and pancreatic patient gene expression data. Analysis of selected genes suppressed by HOTAIR in Panc1 and L3.6 pL cells showed by knockdown of EZH2 and chromatin immunoprecipitation assays that HOTAIR-mediated gene repression was both PRC-2-dependent and -independent. HOTAIR knockdown in L3.6pL cells also inhibited tumor growth in mouse xenograft model, further demonstrating the pro-oncogenic function of HOTAIR in pancreatic cancer. These results indicated that HOTAIR is a potential molecular target for inhibiting pancreatic cancer cell invasion, metastasis and proliferation for inducing cell death. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 203. doi:1538-7445.AM2012-203