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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 281

stable disease. The predominant toxicities were fatigue and myelosuppression. Correlative studies indicated
that DNA methylation of the human leukocyte antigen death receptor 4 (DR4) in peripheral blood leukocytes
was decreased during treatment in three of four objective responders, but in only five of 13 non-responders. In
a phase 2 clinical trial, Matei et al. tested the clinical and biological activity of decitabine administered before
[24]
carboplatin in platinum-resistant ovarian cancer patients. Low-dose decitabine altered DNA methylation along
with the Wnt signaling and apoptosis pathways, restored the sensitivity to carboplatin in patients with heavily
pretreated ovarian cancer and resulted in a high response rate and prolonged progression-free survival (PFS).
Demethylation of the DNA mismatch repair gene MLH1, the tumor suppressor genes RASSF1A, HOXA10 and
HOXA11 in tumors positively correlated with PFS.

Using an ovarian cancer cell line with acquired resistance to carboplatin and genome-wide microarray
profiling, Coley et al. identified the CDK inhibitor p57 (Kip2) to be downregulated in carboplatin
[36]
resistance. Methylation sites in the p57 promoter and even, a preferential sensitivity to seliciclib, a CDK
inhibitor, were detected in the cell line. Silencing of p57 decreased the apoptotic response to the effects of
platinum, but unexpectedly produced sensitization to seliciclib. High levels of p57 mRNA in tumor biopsies
correlated with complete responses to chemotherapy and improved outcome.

The serine proteases urokinase plasminogen activator and tissue-type plasminogen activator together with
their major physiological inhibitor, plasminogen activator inhibitor-1 [PAI-1; serine protease inhibitor clade
E member 1 (SERPINE1)] have been identified as prognostic factors for disease progression and relapse in
different cancer types since they play important roles in cell adhesion, migration and invasion . Recently,
[81]
Pan et al. revealed that that SERPINE1 may be a promising therapeutic target for chemo-resistance of
[82]
ovarian cancer cells. Microarray screening showed that carboplatin treatment caused hypomethylation of
the promoter of SERPINE1, and consequently, significantly increased the expression of SERPINE1, resulting
in induction of the EMT process with decreased expression of E-cadherin and increased expression of
Vimentin, Snail and Twist.

As reported by Syed et al. , DNA methylation of the Polo-like kinase Plk2 in tumor tissues and serum
[37]
samples was associated with a higher risk of relapse in patients treated postoperatively with carboplatin and
paclitaxel. They found that platinum resistance can be conferred by the downregulation of Plk2 transcripts
via promotor methylation in ovarian cancer cells selected for paclitaxel and carboplatin resistance, primary
tumors and patient sera. In the drug-resistant cells, Plk2 promoter methylation varied with the degree of
drug resistance and transcriptional silencing of the promoter. Knockdown of Plk2 abrogated G2-M cell-cycle
blockade by paclitaxel, conferring resistance to both paclitaxel and platinum. Contrary, ectopic expression of
Plk2 restored sensitivity to G2-M cell cycle blockade and cytotoxicity triggered by paclitaxel.

Furthermore, Iramaneerat et al. demonstrated that the expression levels of human endogenous retrovirus
[38]
(HERV) K and E were increased in tissues from patients with ovarian clear cell carcinoma (OCCC).
Methylation levels of HERV were associated with treatment response and prognosis of OCCC. DNA
methylation levels of HERV-K, HERV-E and LINE-1 were decreased in tissues from patients with advanced
stage cancer. In particular, HERV-K was significantly less methylated in the platinum-resistant cohort.
Hypomethylation of HERV-K correlated with a shorter overall and progression-free survival.

Apart from genetic events, epigenetic modification of the SFRP family has been shown to be important
in regulating the Wnt signaling pathway . Su et al. demonstrated that restoration of SFRP5 expression
[48]
[39]
attenuated Wnt signaling in ovarian cancer cells. Cancer cell growth, invasion of cells and tumorigenicity
were inhibited in mice independently of the canonical pathway. Epigenetic silencing of SFRP5 led to
oncogenic activation of the Wnt pathway and contributed to ovarian cancer progression and carboplatin
resistance through the transcription factor Twist-mediated EMT and AKT2 signaling.