SLC 25A26 overexpression impairs cell function via mt DNA hypermethylation and rewiring of methyl metabolism
Alessio Mengaa b, Erika Mariana Palmieric d, Antonia Cianciullic d, Vittoria Infantinoe f, Massimiliano Mazzoneg h, Antonio Scilimatii j, Ferdinando Palmieric d, Alessandra Castegnaa b c d✉, Vito Iacobazzic d✉
- aNational Cancer Research Center Istituto Tumori ‘Giovanni Paolo II’ Bari Italy
- bNational Cancer Research Center, Istituto Tumori 'Giovanni Paolo II', Bari, Italy
- cDepartment of Biosciences Biotechnologies and Biopharmaceutics University of Bari ‘Aldo Moro’ Italy
- dDepartment of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari 'Aldo Moro', Italy
- eDepartment of Science University of Basilicata Potenza Italy
- fDepartment of Science, University of Basilicata, Potenza, Italy
- gLaboratory of Molecular Oncology and Angiogenesis Department of Oncology Vesalius Research Center KU Leuven Belgium
- hLaboratory of Molecular Oncology and Angiogenesis, Department of Oncology, Vesalius Research Center, KU Leuven, Belgium
- iDepartment of Pharmacy University of Bari ‘Aldo Moro’ Italy
- jDepartment of Pharmacy, University of Bari 'Aldo Moro', Italy
- ✉Corresponding author
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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.