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Page 216 Jia et al. Cancer Drug Resist 2019;2:210-24 I http://dx.doi.org/10.20517/cdr.2018.010

catalytic domain that causes centrosome amplification above background levels when overexpressed . This
[16]
may be due to the loss of self-destruction of PLK4.

Acetylation
Acetylation and deacetylation are highly common posttranslational modifications. Several studies
demonstrate that acetylation/deacetylation play a role in the regulation of centrosome duplication and
induction of abnormal amplification of centrosomes. KAT2A/KAT2B function as histone acetyltransferase
or lysine acetyltransferases. Fournier and her colleagues showed that KAT2A/2B acetylate the PLK4 kinase
domain on residues K45 and K46 . Impairing KAT2A/2B-acetyltransferase activity results in diminished
[79]
phosphorylation of PLK4 and in excess centrosome numbers in cells. Therefore KAT2A/2B acetylation
of PLK4 prevents centrosome amplification. On the other hands, through focusing on the deacetylases,
Fukasawa’s group found that the deacetylation event negatively controls centrosome duplication and
amplification. Of the 18 total known deacetylases (HDAC1-11, SIRT1-7), ten deacetylases possess the activity
to suppress centrosome amplification, and their centrosome amplification suppressing activities are strongly
associated with their abilities to localize to centrosomes. Among them, HDAC1, HDAC5 and SIRT1 show
the highest suppressing activities, but each of them suppresses centrosome duplication and/or amplification
with its unique mechanism .
[80]
Methylation
G9a is a histone methyltransferase enzyme, also known as euchromatic histone-lysine N-methyltransferase
2 (EHMT2) . G9a catalyzes the mono- and di-methylated states of histone H3 at lysine residue 9 (i.e.,
[81]
H3K9me1 and H3K9me2) and lysine residue 27 (H3K27me1 and HeK27me2). G9a plays a critical role in
regulating centrosome duplication. Knockdown of G9a significantly reduces di- and trimethylation of
H3K9, resulting in disruptions in centrosome amplification and chromosome instability in cancer cells .
[82]
Furthermore, silencing G9a leads to down-modulation of gene expressions, including that of p16INK4A. It
has been shown that cells lacking p16 (INK4A) activity exhibit phenotypes associated with malignancy .
[83]
p16INK4A is the CDK2, Cdk4 and Cdk6-specific inhibitor . The observations of the effects on G9a
[84]
silencing are in support of the studies linking cyclin D1/Cdk4 with centrosome amplification [85,86] . Initiation
of tumorigenesis was found in the loss of p16INK4A through hypermethylation of its promoter [87-89] . Thus, it
has been postulated that loss of p16 expression coupled with increased γ-tubulin contributes to centrosome
amplification and breast cancer progression .
[90]

14-3-3 proteins are associated with centrosomes . 14-3-3γ prevents centrosome amplification and neoplastic
[91]
progression . Inactivation of the 14-3-3 sigma gene is associated with 5’ CpG island hypermethylation in
[92]
human cancers [93,94] . Promoter hypermethylation of p53 genes is detected in many cancers [95-97] .

Promoter
There is a functional link between centrosome and transcription factors. NF-κB can induce abnormal
centrosome amplification by upregulation of CDK2 . A functional NF-κB binding site was located in the
[98]
CDK2 promoter.

Methyl-CpG binding protein 2 (MeCP2) localizes at the centrosome. Its loss causes deficient spindle
morphology and microtubule nucleation. In addition, MECP2 binds to histone deacetylases and represses
gene transcription .
[99]
E2Fs affect the expression of proteins, including Nek2 and Plk4, thereby deregulation of E2Fs induces
centrosome amplification in breast cancer . A further example showed that arsenic induced centrosome
[100]
amplification via SUV39H2-mediated epigenetic modification of E2F1 .
[101]