Journal
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS
Volume 1863, Issue 9, Pages 1142-1152Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbalip.2018.06.015
Keywords
AGPAT2; LPAAT-beta; HIF-1; Hypoxia; Triglyceride synthesis; Lipid droplets
Funding
- ARISTEIA II Action of the OPERATIONAL PROGRAMME EDUCATION AND LIFELONG LEARNING - European Social Fund (ESF)
- National Resources [3129]
- Research Committee of the University of Thessaly [5309.17.03]
- Hellenic State Scholarship Foundation (IKY)
- ESF
- Greek State
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Hypoxia inducible factor-1 (HIF-1) supports survival of normal cells under low oxygen concentration and cancer cells in the hypoxic tumor microenvironment. This involves metabolic reprogramming via upregulation of glycolysis, downregulation of oxidative phosphorylation and, less well documented, effects on lipid metabolism. To investigate the latter, we examined expression of relevant enzymes in cancer cells grown under hypoxia. We show that expression of acylglycerol-3-phosphate acyltransferase 2 (AGPAT2), also known as lysophosphatidic acid acyltransferase beta (LPAAT beta), was upregulated under hypoxia and this was impaired by siRNA-mediated knockdown of HIF-1 alpha. Moreover, a sequence of the AGPAT2 gene promoter region, containing 6 putative Hypoxia Response Elements (HREs), activated transcription of a reporter gene under hypoxic conditions or in normoxic cells over-expressing HIF-1 alpha. Chromatin immunoprecipitation experiments confirmed binding of HIF-1 alpha to one of these HREs, mutation of which abolished hypoxic activation of the AGPAT2 promoter. Knockdown of AGPAT2 by siRNA reduced lipid droplet accumulation and cell viability under hypoxia and increased cancer cell sensitivity to the chemotherapeutic etoposide. In conclusion, our findings demonstrate that AGPAT2, which is mutated in patients with congenital generalized lipodystrophy and over-expressed in different types of cancer, is a direct transcriptional target of HIF-1, suggesting that upregulation of lipid storage by HIF-1 plays an important role in adaptation and survival of cancer cells under low oxygen conditions.
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