Metabolic reprogramming is a typical feature of cancer cells aimed at sustaining high-energetic demand and proliferation rate. Here, we report clear-cut evidence for decreased expression of the adipose triglyceride lipase (ATGL), the first and rate-limiting enzyme of triglyceride hydrolysis, in both human and mouse-induced hepatocellular carcinoma (HCC). We identified metabolic rewiring as major outcome of ATGL overexpression in HCC-derived cell lines. Indeed, ATGL slackened both glucose uptake/utilization and cell proliferation in parallel with increased oxidative metabolism of fatty acids and enhanced mitochondria capacity. We ascribed these ATGL—downstream events to the activity of the tumor-suppressor p53, whose protein levels—but not transcript—were upregulated upon ATGL overexpression. The role of p53 was further assessed by abrogation of the ATGL-mediated effects upon p53 silencing or in p53-null hepatocarcinoma Hep3B cells. Furthermore, we provided insights on the molecular mechanisms governed by ATGL in HCC cells, identifying a new PPAR-α/p300 axis responsible for p53 acetylation/accumulation. Finally, we highlighted that ATGL levels confer different susceptibility of HCC cells to common therapeutic drugs, with ATGL overexpressing cells being more resistant to glycolysis inhibitors (e.g., 2-deoxyglucose and 3-bromopyruvate), compared to genotoxic compounds. Collectively, our data provide evidence for a previously uncovered tumor-suppressor function of ATGL in HCC, with the outlined molecular mechanisms shedding light on new potential targets for anticancer therapy.

Forcing ATGL expression in hepatocarcinoma cells imposes glycolytic rewiring through PPAR-α/p300-mediated acetylation of p53 / Di Leo, Luca; Vegliante, Rolando; Ciccarone, Fabio; Salvatori, Illari; Scimeca, Manuel; Bonanno, Elena; Sagnotta, Andrea; Grazi, Gian Luca; Aquilano, Katia; Ciriolo, Maria Rosa. - In: ONCOGENE. - ISSN 0950-9232. - (2018). [10.1038/s41388-018-0545-0]

Forcing ATGL expression in hepatocarcinoma cells imposes glycolytic rewiring through PPAR-α/p300-mediated acetylation of p53

Ciccarone, Fabio;Salvatori, Illari;Sagnotta, Andrea;
2018

Abstract

Metabolic reprogramming is a typical feature of cancer cells aimed at sustaining high-energetic demand and proliferation rate. Here, we report clear-cut evidence for decreased expression of the adipose triglyceride lipase (ATGL), the first and rate-limiting enzyme of triglyceride hydrolysis, in both human and mouse-induced hepatocellular carcinoma (HCC). We identified metabolic rewiring as major outcome of ATGL overexpression in HCC-derived cell lines. Indeed, ATGL slackened both glucose uptake/utilization and cell proliferation in parallel with increased oxidative metabolism of fatty acids and enhanced mitochondria capacity. We ascribed these ATGL—downstream events to the activity of the tumor-suppressor p53, whose protein levels—but not transcript—were upregulated upon ATGL overexpression. The role of p53 was further assessed by abrogation of the ATGL-mediated effects upon p53 silencing or in p53-null hepatocarcinoma Hep3B cells. Furthermore, we provided insights on the molecular mechanisms governed by ATGL in HCC cells, identifying a new PPAR-α/p300 axis responsible for p53 acetylation/accumulation. Finally, we highlighted that ATGL levels confer different susceptibility of HCC cells to common therapeutic drugs, with ATGL overexpressing cells being more resistant to glycolysis inhibitors (e.g., 2-deoxyglucose and 3-bromopyruvate), compared to genotoxic compounds. Collectively, our data provide evidence for a previously uncovered tumor-suppressor function of ATGL in HCC, with the outlined molecular mechanisms shedding light on new potential targets for anticancer therapy.
2018
Molecular Biology; Genetics; Cancer Research
01 Pubblicazione su rivista::01a Articolo in rivista
Forcing ATGL expression in hepatocarcinoma cells imposes glycolytic rewiring through PPAR-α/p300-mediated acetylation of p53 / Di Leo, Luca; Vegliante, Rolando; Ciccarone, Fabio; Salvatori, Illari; Scimeca, Manuel; Bonanno, Elena; Sagnotta, Andrea; Grazi, Gian Luca; Aquilano, Katia; Ciriolo, Maria Rosa. - In: ONCOGENE. - ISSN 0950-9232. - (2018). [10.1038/s41388-018-0545-0]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1184823
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