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Schwarzenbach et al. Cancer Drug Resist 2019;2:271-96 I http://dx.doi.org/10.20517/cdr.2019.010 Page 283

Cisplatin resistance
There are a few articles on the relationship of histone modifications to platinum resistance. In this regard,
Cacan et al. identified HDAC and DNMT1 to exhibit an aberrant association with the regulator of G
[92]
protein signaling 10 (RGS10) in chemoresistant ovarian cancer cells. Knockdown of HDAC1 or DNMT1
expression and pharmacological inhibition of DNMT or HDAC enzymatic activity significantly increased
RGS10 expression and cisplatin-mediated cell death. Moreover, DNMT1 knockdown decreased HDAC1
binding to the RGS10 promoter in chemo-resistant cells, suggesting HDAC1 recruitment to RGS10 promoters
requires DNMT1 activity.

In both in vitro (cisplatin-resistant ovarian cancer cells) and in vivo (xenografts), Steele et al. observed that
[93]
the combination of decitabine and a clinically relevant inhibitor of HDAC activity (belinostat) increased the
expression of epigenetically silenced MLH1 gene and MAGE-A1 antigen when compared with decitabine
alone. The treatment that influenced the histone structure improved the efficacy of chemotherapy in tumors
that had acquired drug resistance due to DNA methylation and gene silencing. Liu et al. also performed
[94]
in vitro and in vivo studies. In cisplatin-resistant ovarian cancer cells, they showed that HDAC1 knockdown
suppressed cell proliferation and increased apoptosis. The increase in chemo-sensitivity was caused by
downregulating the oncogene c-Myc and upregulating miR-34a. Cisplatin treatment activated HDAC1
and c-Myc and inactivated miR-34a. Inhibition of HDAC1 reduced c-Myc expression, increased miR-34a
expression and sensitized ovarian cancer cells to cisplatin-induced apoptosis. In vivo studies confirmed these
findings. They showed that targeting HDAC1 sensitized murine xenograft models to cisplatin treatment.
Cacan demonstrated that expression of the death receptor FAS is suppressed in cisplatin resistant
[95]
ovarian cells compared to parental cells. Surprisingly, no difference in DNA methylation was observed
at FAS promoters between both cell lines. However, there were a decrease in acetylated histone H3 and a
corresponding increase in HDAC1 associated with FAS promoter in resistant cells. Knockdown of HDAC1
and pharmacological inhibition of HDAC enzymatic activity significantly increased FAS expression in
resistant cells, suggesting that particularly histone modifications may contribute to the loss of FAS expression
in cisplatin resistant ovarian cancer cells, and that enhancement of FAS expression may increase tumor cell
sensitivity to immune cells.

Histone modifications in chemo-resistant cells were evaluated in relationship to oncolytic adenovirus
efficacy by Hulin-Curtis et al. . In contrast to cisplatin-sensitive ovarian cells displaying an efficient
[96]
shortening of cell viability by adenovirus in the presence of cisplatin, cisplatin-resistant cells diminished this
reduction of cell viability mediated by adenovirus with increasing doses of cisplatin. HDAC2, and to a lesser
extent HDAC1, were up-regulated in cisplatin-resistant but not in cisplatin-sensitive cells. Administration
of cisplatin-resistant cells with trichostatin A (TSA), a HDAC inhibitor significantly enhanced adenovirus
mediated reduction of cell viability in the presence of cisplatin. Cells treated with TSA alone did not display
this effect, indicating an adenovirus dependent mechanism.

Carboplatin resistance
In a phase I trial, Falchook et al. demonstrated that sequential treatment with a combination of the
[97]
nucleoside analogue azacytidine, the HDAC valproic acid and carboplatin decreased DR4 methylation, but
there was no relationship with either tumor response or number of therapy cycles received. A modest evidence
of antitumor activity could only be observed in patients with heavily treated advanced malignancies.

MICRORNAS
Besides DNA methylation, the dysregulation of microRNAs (miRNAs) may also be responsible for the
induction of acquired platinum resistance in ovarian cancer. MiRNAs are, together with long non-coding
RNAs (lncRNAs) and small RNAs, members of the non-coding RNAs (ncRNAs) . Whilst lncRNAs have
[98]
been confirmed to be epigenetically modified, it is only recently that miRNA epigenetic modifications have