HOTAIR is a negative prognostic factor and exhibits pro-oncogenic activity in pancreatic cancer

Abstract

HOTAIR is a long intervening non-coding RNA (lincRNA) that associates with the Polycomb Repressive Complex 2 (PRC2) and overexpression is correlated with poor survival for breast, colon and liver cancer patients. In this study, we show that HOTAIR expression is increased in pancreatic tumors compared to non-tumor tissue and is associated with more aggressive tumors. Knockdown of HOTAIR (siHOTAIR) by RNA interference shows that HOTAIR plays an important role in pancreatic cancer cell invasion and as reported in other cancer cell lines. In contrast, 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 array studies 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 gene sets related to cell cycle progression in pancreatic cancer cells and tumors. 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 PRC2-dependent and -independent. HOTAIR knockdown in L3.6pL cells inhibited tumor growth in mouse xenograft model, further demonstrating the pro-oncogenic function of HOTAIR in pancreatic cancer.

HOTAIR Epigenetically Modulates PTEN Expression via MicroRNA-29b: A Novel Mechanism in Regulation of Liver Fibrosis

“…16,17 Accumulating studies have indicated that HOTAIR is upregulated in cancers including HCC. [18][19][20] It has been reported that HOTAIR regulates gene expression via epigenetic modifications. 21 For example, Rinn et al demonstrated that HOTAIR interacts with polycomb-repressive complex 2 (PRC2) to increase the trimethylation of histone H3 lysine-27 (H3K27), resulting in the reduction of HOXD gene expression.…”

Long non-coding RNAs in colorectal cancer: implications for pathogenesis and clinical application

“…11,16 In fact, previous studies have shown that particular deregulated lncRNAs are important regulators of tumor formation and progression. 17,24 For example, the antisense intergenic RNA HOX Antisense Intergenic RNA (HOTAIR) is highly expressed in multiple types of primary somatic tumors, such as hepatocellular carcinoma, 25,26 pancreatic cancer, 27 and gastric cancer, 28 as well as some metastatic tumors, including metastatic breast tumors 29 and melanoma. 30 Moreover, high HOTAIR level is associated with poor patient survival rate 20,27 and tumor recurrence.…”

“…17,24 For example, the antisense intergenic RNA HOX Antisense Intergenic RNA (HOTAIR) is highly expressed in multiple types of primary somatic tumors, such as hepatocellular carcinoma, 25,26 pancreatic cancer, 27 and gastric cancer, 28 as well as some metastatic tumors, including metastatic breast tumors 29 and melanoma. 30 Moreover, high HOTAIR level is associated with poor patient survival rate 20,27 and tumor recurrence. 25 It was discovered that HOTAIR represses transcription across 40 kb of the HOXD locus by acting as a scaffold of histone modification complexes; it binds with polycomb chromatin remodeling complexes in trans, which lead to alterations of cells' epigenetic state and subsequent gene expression.…”

LncRNA HOTAIR/miR‐613/c‐met axis modulated epithelial‐mesenchymal transition of retinoblastoma cells

“…Of note, a microarray analysis confirmed that lncRNAs HOX antisense intergenic RNA (HOAIR), CCAT1 and HIF1A‐AS1 were over‐expressed within retinoblastoma tissues, yet lncRNAs MIR31HG, BCAR4 and H193 were evidently under‐expressed within retinoblastoma tissues 13. Among them, HOTAIR was identified to be a cis‐acting parameter within the HOXC loca,14, 15, 16 and its carcinogenicity has been authenticated within breast cancer, liver cancer, colorectal cancer, oesophageal squamous cancer, pancreatic cancer, non‐small cell lung cancer and cervical cancer 17, 18, 19, 20, 21, 22, 23, 24. In addition, HOAIR was indicated as a potential therapeutic biomarker for retinoblastoma, and silencing of HOTAIR could attenuated proliferation, migration and invasion of retinoblastoma cells were determined after 25…”