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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 7 of 14

encoded by the Tmem70 gene, is a protein of the mitochondrial inner membrane that participates in
mitochondrial biogenesis and whose mutations can be associated with the deficiency in the synthesis of
ATP [70,71] . MRPS12 is a mitoribosomal conserved protein and MGRAP is an important protein for the
[72]
maintenance of mitochondrial morphology and quantity, as well as for the process of steroidogenesis .
[73]
Enzymes that catalyze acetylation, methylation, or their loss also regulate epigenetic changes [74,75] . For
example, the enzyme LSD1 (lysine-specific demethylase 1) uses the mitochondrial cofactor FAD to carry out
the demethylation of modified histones such as H3K4me1 and H3K4me2 .
[76]

LSD1 has been proposed as a regulator of cell proliferation in several cancer types, as well as its metabolic
reprogramming [77,78] . In HCC, it has been determined that LSD1 regulates energy production and suppresses
mitochondrial respiration . These studies also determined that the demethylase activity by LSD1 represses
[78]
mitochondrial metabolism genes and induces the expression of glycolytic genes .
[78]
In HCC, differential expression of different miRNAs has been observed, as well as epigenetic modifications .
[79]

miR-122 regulation of PGC-1α (peroxisome proliferator activated receptor gamma, coactivator 1 alpha) and
SDH (succinate dehydrogenase) subunits A and B is necessary for mitochondrial metabolism. In HCC, this
miRNA is scarcely expressed. Studies propose this microRNA as a tumor suppressor, since in primary HCC
tumors, in both human and rodents, it is seen at low levels, compared to its healthy controls. Also, in HBV-
infected patients, this miRNA is reduced in hepatic tissue [45,80,81] . miR-122 is implicated in the control of lipid
metabolism and circadian regulation in the liver. This microRNA has been observed in steatohepatitis and
liver fibrosis, in addition to HCC [80,82] . Experimentally, the genetic deletion of miR-122 in mice has important
effects on lipid metabolism, as well as on the progression of liver disease, from microsteatosis to HCC [80,82] .

miR-33a/b regulates lipid metabolism through the ABCA1 cholesterol transporter. Its overexpression inhibits
the oxidation of fatty acids in the liver cancer cell line HuH7, favoring the accumulation of triglycerides in
larger lipid droplets. MiR-33 binding sites have been identified in the 3 'UTR of genes for mitochondrial
proteins such as carnitine O-octaniltransferase (CROT) and carnitine palmitoyltransferase 1A (CPT1a).
This miRNA inhibits also the insulin receptor substrate 2 (ISR2) and regulates insulin signaling [83,84] . There
is very little information about the role of this miRNA in HCC, so we suggest that this could be studied more
extensively to determine its importance in this pathology.

On the other hand, the role of mitochondrial genetic alterations has been investigated in HCC, and tumors
contained significantly reduced mtDNA and TFAM overexpression, although neither condition correlated
with the degree of cell differentiation; TFAM expression correlated with tumor size .
[85]
For all the above, the field of mitoepigenetics has attracted research with the aim of having more effective
therapeutic targets in the treatment of HCC.

Mitoepigenetics in tumor-initiating stem-like cells in HCC
The liver cancer, as other epithelial cancers, has tumor-initiating stem-like cells (TICs) that are implicated
in tumorigenesis and drug resistance . TICs share some characteristics with embryonic stem cells (ESC)
[86]
including expression of the pluripotency transcription factors, NANOG, OCT4, MYC, and SOX2. The
expression of pluripotency transcription factors contributes to cancer progression by reprogramming
mitochondrial metabolism [87,88] .

NANOG represses OXPHOS genes, prevents mitochondrial ROS production, and activates fatty acid oxidation
(FAO), contributing to TIC self-renewal and drug resistance . Low levels of ROS are necessary to preserve
[87]