The long non-coding RNA HOTAIR enhances pancreatic cancer resistance to TNF-related apoptosis-inducing ligand
| Autor: | Yabing Chen, Jay M. McDonald, Xinyang Zhao, Fei Xu, Shan-zhong Yang, Tong Zhou |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Apoptosis Biology Biochemistry Methylation Histones TNF-Related Apoptosis-Inducing Ligand 03 medical and health sciences 0302 clinical medicine Pancreatic cancer Cell Line Tumor Histone methylation medicine Humans Enhancer of Zeste Homolog 2 Protein Epigenetics RNA Neoplasm Molecular Biology Gene knockdown EZH2 HOTAIR Molecular Bases of Disease Cell Biology medicine.disease Long non-coding RNA Neoplasm Proteins Gene Expression Regulation Neoplastic Pancreatic Neoplasms Receptors TNF-Related Apoptosis-Inducing Ligand 030104 developmental biology Drug Resistance Neoplasm 030220 oncology & carcinogenesis Cancer research RNA Long Noncoding HOX Transcript Antisense RNA |
| Zdroj: | The Journal of biological chemistry. 292(25) |
| ISSN: | 1083-351X |
| Popis: | Pancreatic cancer is a malignant neoplasm with a high mortality rate. Therapeutic agents that activate TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis have shown promising efficacy, but many pancreatic cancers are resistant to TRAIL therapy. Epigenetic regulation plays important roles in tumor pathogenesis and resistance, and a recent study indicated that the long non-coding RNA HOX transcript antisense RNA (HOTAIR) is overexpressed in pancreatic cancer. However, the role of HOTAIR in pancreatic cancer resistance to anticancer agents is unknown. The present study determined the role of HOTAIR in pancreatic cancer TRAIL resistance and investigated the underlying molecular mechanisms. We observed that TRAIL-resistant pancreatic cancer cells had higher levels of HOTAIR expression, whereas TRAIL-sensitive pancreatic cancer cells had lower HOTAIR levels. Overexpressing HOTAIR in TRAIL-sensitive cells attenuated TRAIL-induced apoptosis, and shRNA-mediated HOTAIR knockdown in TRAIL-resistant PANC-1 cells sensitized them to TRAIL-induced apoptosis. These results support a causative effect of HOTAIR on TRAIL sensitivity. Mechanistically, we found that increased HOTAIR expression inhibited the expression of the TRAIL receptor death receptor 5 (DR5), whereas HOTAIR knockdown increased DR5 expression. We further demonstrated that HOTAIR regulates DR5 expression via the epigenetic regulator enhancer of zeste homolog 2 (EZH2) and that EZH2 controls histone H3 lysine 27 trimethylation on the DR5 gene. Taken together, these results demonstrate that high HOTAIR levels increase the resistance of pancreatic cancer cells to TRAIL-induced apoptosis via epigenetic regulation of DR5 expression. Our study therefore supports the notion that targeting HOTAIR function may represent a strategy to overcome TRAIL resistance in pancreatic cancer. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|