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Jia et al. Cancer Drug Resist 2019;2:210-24 I http://dx.doi.org/10.20517/cdr.2018.010 Page 217

DDX3 regulates epigenetic transcriptional and translational activation of p53 and colocalizes with p53 at
centrosome during mitosis to ensure proper mitotic progression and genome stability, which supports the
tumor-suppressive role of DDX3 . DDX3 knockdown suppressed p53 transcription through activation
[102]
of DNA methyltransferases along with hypermethylation of p53 promoter and promoting the binding of
repressive histone marks to p53 promoter.

During tumor development, especially to most solid tumors, cancer cells are often subjected to hypoxia .
[103]
A recent study showed that via upregulation of HIF1, proteins whose overexpression drives centrosome
amplification (such as Cyclin E, Aurora A, and PLK4) were upregulated .
[104]

MiRNA
Recently gene expression of centrosome proteins was found as miRNA targets. MiR-129-3p is identified as a
novel metastatic microRNA. CP110 expression was repressed by miR-129-3p .
[105]
PLK1 is one of targets of miRNA-210-3p, and lnc-RI regulates PLK1 mRNA stability by competing with the
PLK1 mRNA 3’UTR for binding to miRNA-210-3p .
[106]
MiR-128 inhibited NEK2 expression and miR-128 was silenced by DNA methylation. Up-regulation of NEK2
by MicroRNA-128 methylation is associated with poor prognosis in colorectal cancer .
[107]

Ubiquitination
Dysfunction in the ubiquitin-proteasome degradation has implicated in several cancer drug resistance.
MDM2 is an E3 ubiquitin-protein ligase that mediates ubiquitination and degradation of p53 [108,109] . Increased
levels of MDM2 would inactivate the functions of p53 to similar extent that do in deletion or mutation of
p53 and found in a variety of human tumors . Several studies demonstrated that MDM2 overexpression
[110]
increases cancer drug resistance of tumors [111,112] . Mind bomb (Mib1) was identified as the E3 ubiquitin ligase
of PLK4 . Recently we found that HECTD1, a HECT-type E3 ubiquitin ligase is a novel centrosome protein
[113]
whose deficiency induces centrosome amplification and promotes epithelial-mesenchymale transition [114,115] .
These results indicate ubiquitination is one of the important epigenetic modifications for centrosome.

NEW DRUGS IN TRIAL
Abnormalities in size, number and microtubule nucleation capacity of centrosome are resulted from genetic
disorders or epigenetic disturbances of gene expression. Epigenetic modifications are temporally dynamic
and reversible changes. Development of small molecules targeting epigenetic regulators are promising
anticancer strategies, involving elimination of cancer cells with chromosome instability and aneuploid
in combination with targeting centrosome proteins to overcome mitotic slippage and to induce apoptosis
in cancer cells. The drugs that focused on the centrosome amplification may provide possibilities to treat
cancer or overcome some forms of drug resistance. Recently clinical trials of inhibitors targeting kinases
that function as centrosome regulators are under way for hematologic malignancies and solid tumors. We
summarize the development of therapies targeting these mechanisms.

Although a lot of progresses have been made in treating cancer, the most cancer chemotherapeutics develop
drug resistant (secondary) that limits the efficacy of treatments. This happened even for the newly approved
NTRK inhibitors . Thus, there is a significant need to target drug resistance for improved therapeutics for
[116]
cancer. Several clinical trials, in single or combination of drugs, have been focused on blocking centrosome
clustering to combat drug resistance [Table 2].

Since increased levels of MDM2 inactivate the functions of p53 thereby induce centrosome amplification
and drug resistance. Inhibition of MDM2 is obviously a good strategy to fight cancer drug resistance. Several