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.

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

Mazzone M.;
2017-01-01

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.
2017
epigenetic mechanisms
methyl cycle
mtDNA methylation
S-adenosylmethionine
SLC25A26 mitochondrial carrier
Adenosine Triphosphate
Amino Acid Transport Systems
Apoptosis
Calcium-Binding Proteins
Cell Cycle
Cell Line
Tumor
Cell Proliferation
Cisplatin
Cytochromes c
DNA Methylation
DNA
Mitochondrial
Drug Resistance
Neoplasm
Female
Gene Expression Regulation
Neoplastic
Glutathione
Humans
Methionine
Mitochondria
Promoter Regions
Genetic
S-Adenosylmethionine
Uterine Cervical Neoplasms
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11699/83129
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