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Page 6 of 14 Lozano-Rosas et al. Hepatoma Res 2018;4:19 I http://dx.doi.org/10.20517/2394-5079.2018.48

change in the levels of an enzyme called MAT that catalyzes the formation of SAM has been implicated also.
MAT is encoded by two genes, Mat1a and Mat2a. In HCC, the liver decreases the amount of MAT1A and
increases MAT2A through epigenetic mechanisms alone; this switch is responsible for the decreasing level
of SAM, favoring the development of this pathology [61,62] .

Due to the above, it is necessary not only to consider the epigenetic modifications but also the generation of
intermediaries by mitochondria that allow for the appropriate epigenetics control of both the mtDNA and
the nDNA.

Altered mitoepigenetics in HCC
As afore mentioned, NRF1 and PGC1-α act on nuclear genes encoding respiratory subunits from ETC and
are involved in the transcription and replication machinery. An up-regulation of this protein in HCC has
been demonstrated [8,63] . An increased PGC1α level has been suggested to be an important inducer for the
accumulation of dysfunctional mitochondria . Although the role of pgc1-α and nrf1 genes methylation has
[8]
not been studied in HCC, this is an interesting area to be investigated. A meta-analysis of DNA methylation
in HCC revealed a correlation between several aberrant methylated genes and the risk of HCC, among them
p53 was hypermethylated in HCC tumor tissue compared to the adjacent tissue. It is important to consider
that, in turn, this gene is implicated in the transcription and translocation of mtDNMT1 to mitochondria,
and, in this way, besides of its role as tumor suppressor it could be modulating the methylation status of
mitochondrial genes .
[64]
Under conditions of oxidative stress, which may be a factor for the development of HCC, the transcriptional
and mitochondrial DNA replication machinery is altered. Consequently, the ETC loses its functionality
and favors the accumulation of reactive oxygen species (ROS). In addition, the mtDNA may suffer injuries
because of the accumulation ROS [1,65] . On the other hand, the mitochondrial damage observed in cancer cells
can have consequences on the expression of nuclear genes. There are studies that indicate that the removal
of mtDNA responds to changes in the nuclear genome [56,66] .

A genome-wide mapping of DNA methylation and hydroxymethylation in a study on HBV-related HCC
revealed that the metabolic pathways that include glycolysis, gluconeogenesis, oxidative phosphorylation,
and TCA contained the largest number of (hydroxy) methylation-altered genes, indicating the crucial roles of
metabolic processes that implicate mitochondria in the progression of HCC, which, in turn, are regulated by
epigenetic mechanisms. The authors propose that some of the identified (hydroxy) methylation-altered genes
may serve as biomarkers for the diagnosis and prognosis of HCC . Among the 5-mC and 5-hmC altered
[67]
genes related to OXPHOS were the following: NADH dehydrogenase [ubiquinone] 1 subunit C2 (NDUFC2),
NADH dehydrogenase [ubiquinone] flavoprotein 1 (NDUFV1), NADH: ubiquinone oxidoreductase subunit
S6 (NDUFS6) from complex 1 and succinate dehydrogenase complex flavoprotein subunit A (SDHA)
from complex II. Among the TCA genes: succinyl-CoA ligase [GDP-forming] subunit beta (SUCLG2) and
pyruvate carboxylase.

Also, in HBV-induced hepatic carcinogenesis, protein X (HBx), encoded by the virus, has been proposed
as an epigenetic regulator for tumor suppressor genes, by hypermethylation. It has been suggested that,
in hepatomas, NQO1 (NAD(P)H: quinone oxidoreductase 1), which is a cytosolic protein that catalyzes
two-electron reduction, can be deregulated by induction of HBx, generating mitochondrial damage and
increasing oxidant stress in cells through hypermethylation of the NQO1 promoter .
[68]
Specifically in mitochondria, some epigenetic modifications have been described in HCC, such as
hypermethylation of the Mrps12 (mitochondrial ribosomal protein S12), Mgrap (mitochondria-localized
glutamic acid-rich protein), and Tmem70 (transmembrane protein 70) genes . The TMEM70 protein,
[69]