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SLC25A26 overexpression impairs cell function via mtDNA hypermethylation and rewiring of methyl metabolism.

Research paper by Alessio A Menga, Erika M EM Palmieri, Antonia A Cianciulli, Vittoria V Infantino, Massimiliano M Mazzone, Antonio A Scilimati, Ferdinando F Palmieri, Alessandra A Castegna, Vito V Iacobazzi

Indexed on: 25 Jan '17Published on: 25 Jan '17Published in: FEBS Journal



Abstract

Cancer cells down-regulate different genes to take a selective advantage towards invasiveness and/or metastasis formation. The SLC25A26 gene, encoding for the mitochondrial carrier that catalyzes the import of S-adenosylmethionine (SAM) into the mitochondrial matrix required for mitochondrial methylation processes, 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, SLC25A26 (SAMC) overexpression in CaSki cells increases mitochondria SAM availability and promotes hypermethylation of mtDNA, 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 expenses of glutathione, which is strongly reduced. All these events concur to arrest the cycle cell in the S phase, induce apoptosis and enhance chemiosensitivity of SAMC-overexpressing CaSki cells to cisplatin. This article is protected by copyright. All rights reserved.