title: SLC25A26 overexpression impairs cell function via mtDNA hypermethylation and rewiring of methyl metabolism.
abstract: Cancer cells down-regulate different genes to give them a selective advantage in invasiveness and/or metastasis. The SLC25A26 gene encodes the mitochondrial carrier that catalyzes the import of S-adenosylmethionine (SAM) into the mitochondrial matrix, required for mitochondrial methylation processes, and is down-regulated in cervical cancer cells. In this study we show that SLC25A26 is down-regulated due to gene promoter hypermethylation, as a mechanism to promote cell survival and proliferation. Furthermore, overexpression of SLC25A26 in CaSki cells increases mitochondrial SAM availability and promotes hypermethylation of mitochondrial DNA, leading to decreased expression of key respiratory complex subunits, reduction of mitochondrial ATP and release of cytochrome c. In addition, increased SAM transport into mitochondria leads to impairment of the methionine cycle with accumulation of homocysteine at the expense of glutathione, which is strongly reduced. All these events concur to arrest the cell cycle in the S phase, induce apoptosis and enhance chemosensitivity of SAM carrier-overexpressing CaSki cells to cisplatin.
authors.affiliation: National Cancer Research Center, Istituto Tumori 'Giovanni Paolo II', Bari, Italy.
authors.forename: Alessio
authors.initials: A
authors.lastname: Menga
authors.affiliation: Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari 'Aldo Moro', Italy.
authors.forename: Erika M
authors.initials: EM
authors.lastname: Palmieri
authors.affiliation: Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari 'Aldo Moro', Italy.
authors.forename: Antonia
authors.initials: A
authors.lastname: Cianciulli
authors.affiliation: Department of Science, University of Basilicata, Potenza, Italy.
authors.forename: Vittoria
authors.initials: V
authors.lastname: Infantino
authors.affiliation: Laboratory of Molecular Oncology and Angiogenesis, Department of Oncology, Vesalius Research Center, KU Leuven, Belgium.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Mazzone
authors.affiliation: Department of Pharmacy, University of Bari 'Aldo Moro', Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Scilimati
authors.affiliation: Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari 'Aldo Moro', Italy.
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Palmieri
authors.affiliation: National Cancer Research Center, Istituto Tumori 'Giovanni Paolo II', Bari, Italy.|Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari 'Aldo Moro', Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Castegna
authors.affiliation: Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari 'Aldo Moro', Italy.
authors.forename: Vito
authors.initials: V
authors.lastname: Iacobazzi
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D026905:Amino Acid Transport Systems / Q000096:biosynthesis* / Q000235:genetics; D017209:Apoptosis / Q000235:genetics; D002135:Calcium-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D002945:Cisplatin / Q000008:administration & dosage; D045304:Cytochromes c / Q000096:biosynthesis* / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008715:Methionine / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics; D011401:Promoter Regions, Genetic; D012436:S-Adenosylmethionine / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D026905:Amino Acid Transport Systems; D002135:Calcium-Binding Proteins; D004272:DNA, Mitochondrial; C487502:SLC25A26 protein, human; D012436:S-Adenosylmethionine; D000255:Adenosine Triphosphate; D045304:Cytochromes c; D008715:Methionine; D005978:Glutathione; D002945:Cisplatin
keywords: S-adenosylmethionine; SLC25A26 mitochondrial carrier; epigenetic mechanisms; methyl cycle; mtDNA methylation