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Lozano-Rosas et al. Hepatoma Res 2018;4:19 I http://dx.doi.org/10.20517/2394-5079.2018.48 Page 9 of 14

associated with various form of cancer, including HCC. Carcinogenesis is a complex process that can be
accompanied by epigenetic modifications. According to what has been described in this review, the epigenetic
regulation of carcinogenesis can be used not only as a biomarker of cancer, but also to determine the stage
of the carcinogenic process, because epigenetic patterns may be associated. Although there is very little
information about mitoepigenetics in HCC, there are data that may be promising as a biomarker and even as
a therapeutic target. The mtDNA heterogeneity epigenetics should be investigated by measuring single-cell
DNA sequencing, comprehensive characterizations of mtDNA, and bidirectional effects between mtDNA
and 3D genome, instability, and gene editing. It would be more helpful to combine the single-cell biology of
CRIPRS to mtDNA function, given that copy number changes can also be regarded as biomarkers in cancer
diagnosis and treatment [99-102] .

Ye et al. reported the methylation and hydroxymethylation profile of DNA in HCC related to HBV;
[67]
they found some hypermethylated genes associated with metabolic pathways. Of these genes, the pc gene
that codes for the enzyme pyruvate decarboxylase (PC) should be considered. PC is a nuclear-encoded
mitochondrial enzyme involved in gluconeogenesis, it catalyzes the conversion of pyruvate to oxaloacetate
in an adenosine triphosphate (ATP)-dependent form. Being a liver-specific enzyme, the hypermethylation of
this gene could provide specificity as a biomarker of HCC.

Further studies are needed to find correlations between mtDNA methylation patterns and HCC in such
a way as to get diagnostic tools through non-invasive techniques. Let us recall the work of Liu et al. , in
[39]
which the detection of mtDNA methylation was below 2% in blood and saliva. However, there are other
mitoepigenetic parameters in which significant correlations have been found with HCC and that point
them out as potential biomarkers, such is the case of miR-122 that has been considered a molecule with
great potential for diagnosis, prognosis of liver disease, and therapy. Studies demonstrated that miR-122 is
reduced in rodent and human primary HCC . Being it a miRNA that regulates hepatic homeostasis and
[103]
having been found under-regulated in diseases. such as HCC, it becomes a possible biomarker and possible
therapeutic target .
[104]

FINAL REMARKS
This review supports the suggestion that disrupted mitoepigenetics may contribute to tumorigenesis.
The next generation experiments may elucidate the functional implications of mtDNA methylation and
hydroxymethylation and could help clarify the role of these epigenetic markers.

The role of mtDNA is pluripotent, because it can affect processes like cellular differentiation, energy
production, oxidative stress, metabolism, inflammation, and carcinogenesis. However, most of these
emerging evidences could be modulated, at least in part, through changes in mitochondria, they could offer
also a new opportunity to understand the causality of cancer [Figure 1].

The studies of the role of mitoepigenetics modifications and the metabolic processes in the pathogenesis
of HCC could be a relevant advancement in the diagnosis and future therapy for this and other types of
cancer.

Given the impact of mitochondrial biology and genome, the mitoepigenetics field offers a new opportunity to
understand mitochondrial diseases and others that are not known as mitochondrial diseases. In addition, the
mitochondrial epigenome also provides new clues for possible therapeutic targets and favors the appearance
of new pharmacological options.