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LINC00842 inactivates transcription co-regulator PGC-1α to promote pancreatic cancer malignancy through metabolic remodelling.
- Source :
-
Nature communications [Nat Commun] 2021 Jun 22; Vol. 12 (1), pp. 3830. Date of Electronic Publication: 2021 Jun 22. - Publication Year :
- 2021
-
Abstract
- The molecular mechanism underlying pancreatic ductal adenocarcinoma (PDAC) malignancy remains unclear. Here, we characterize a long intergenic non-coding RNA LINC00842 that plays a role in PDAC progression. LINC00842 expression is upregulated in PDAC and induced by high concentration of glucose via transcription factor YY1. LINC00842 binds to and prevents acetylated PGC-1α from deacetylation by deacetylase SIRT1 to form PGC-1α, an important transcription co-factor in regulating cellular metabolism. LINC00842 overexpression causes metabolic switch from mitochondrial oxidative catabolic process to fatty acid synthesis, enhancing the malignant phenotypes of PDAC cells. High LINC00842 levels are correlated with elevated acetylated- PGC-1α levels in PDAC and poor patient survival. Decreasing LINC00842 level and inhibiting fatty acid synthase activity significantly repress PDAC growth and invasiveness in mouse pancreatic xenograft or patient-derived xenograft models. These results demonstrate that LINC00842 plays a role in promoting PDAC malignancy and thus might serve as a druggable target.
- Subjects :
- Acetylation
Animals
Carcinoma, Pancreatic Ductal metabolism
Carcinoma, Pancreatic Ductal therapy
Cell Line, Tumor
Female
HEK293 Cells
Humans
Mice, Inbred BALB C
Mice, Nude
Pancreatic Neoplasms metabolism
Pancreatic Neoplasms therapy
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha metabolism
RNA Interference
Sirtuin 1 metabolism
Xenograft Model Antitumor Assays methods
Mice
Carcinoma, Pancreatic Ductal genetics
Energy Metabolism genetics
Gene Expression Regulation, Neoplastic
Pancreatic Neoplasms genetics
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha genetics
RNA, Long Noncoding genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 12
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 34158490
- Full Text :
- https://doi.org/10.1038/s41467-021-23904-4