Epigenetic upregulation and functional role of the mitochondrial aspartate/glutamate carrier isoform 1 in hepatocellular carcinoma

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1865

Article

Infantino, Vittoria^1,2  Dituri, Francesco³  Convertini, Paolo^1,2  Santarsiero, Anna¹  Palmieri, Ferdinando²  Todisco, Simona¹  Mancarella, Serena³  Giannelli, Gianluigi³  Iacobazzi, Vito² 

[1] Univ Basilicata, Dept Sci, Viale Ateneo Lucano 10, I-85100 Potenza, Italy

[2] Univ Bari, Dept Biosci Biotechnol & Biopharmaceut, Via Orabona 4, I-70125 Bari, Italy

[3] S de Bellis Res Hosp, Natl Inst Gastroenterol, Via Turi 27, I-70013 Bari, Italy

关键词: Aspartate-glutamate carrier isoform 1 (AGC1);    SLC25A12;    Hepatocellular carcinoma (HCC);    Epigenetics;    Gene expression;    Cancer metabolism;   

DOI  :  10.1016/j.bbadis.2018.10.018

来源: Elsevier

【 摘 要 】

Metabolic reprogramming is a common hallmark of cancer cells. Although some biochemical features have been clarified, there is still much to learn about cancer cell metabolism and its regulation. Aspartate-glutamate carrier isoform 1 (AGC1), encoded by SLC25A12 gene, catalyzes an exchange between intramitochondrial aspartate and cytosolic glutamate plus a proton across the mitochondrial membrane, so supplying aspartate to the cytosol. SLC25A12, expressed in brain, heart, and skeletal muscle, is silenced in normal liver. Here, we demonstrate that SLC25A12 gene is reactivated in hepatocellular carcinoma (HCC) HepG2 cell line through histone acetylation and CREB recruitment. Furthermore, SLC25A12 knockdown by small interfering RNA, impairs HepG2 cell proliferation by inducing cell cycle arrest. AGC1 sustains HCC cell growth by supplying cytosolic aspartate for nucleotide biosynthesis. In addition, SLC25A12-silenced HCC cells show a strong reduction of cell migration. Overall, we have provided evidence for molecular mechanisms controlling SLC25A12 gene expression in liver and pointing to an important role for AGC1 in HCC.

【 授权许可】

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