Table 4.

Roles of (de-)acetylating enzymes in prostate cancer.

Enzyme	Involvement(s) in Prostate Cancer	Ref.
KATs
KAT2A	KAT2A inhibition prevents interleukin (IL) 6-induced PCa metastases through PI3K/PTEN/AKT signaling by inactivating Egr-1	[307]
	Association between AR and histone acetyltransferase KAT2A increases histone H3 acetylation level on cis-regulatory elements of AR target genes	[308]
KAT2B	Promotes PKM2 acetylation and decreases PKM2 protein level through degradation through chaperone-mediated autophagy; promotes tumor growth	[309]
CBP (KAT3A)	CBP loss cooperates with PTEN haploinsufficiency to drive PCa	[310]
p300 (KAT3B)	p300-mediated acetylation of histone demethylase JMJD1A prevents its degradation by CHIP and enhances its activity	[227]
	p300/CBP inhibition enhances the efficacy of programmed death-ligand 1 blockade treatment	[311]
	Therapeutic targeting of the CBP/p300 bromodomain blocks the growth of CRPC	[312]
	p300 regulates fatty acid synthase expression, lipid metabolism and PCa growth	[313]
	p300 regulates AR degradation and PTEN-deficient prostate tumorigenesis	[314]
	The assembly of a macromolecular complex involving CBP/p300 results in acetylation of p53 at K373, a critical PTM required for its biological activity	[315]
	SKP2 is acetylated by p300 at K68 and K71, which promotes its cytoplasmic retention, and cytoplasmic SKP2 enhances cellular migration through ubiquitination and destruction of E-cadherin	[202]
	p300 is the dominant coregulator of the CBP/p300 pair for androgen-regulated gene expression in C4-2B cells; p300 is required at an early stage of chromatin remodeling and transcription complex assembly after binding of AR to the gene but before many critical histone modifications occur	[316]
	Function in the survival and invasion pathways of PCa cell lines	[317]
	p300 and CBP stimulate estrogen receptor-beta (ER-β) signaling and regulate cellular events in PCa	[318]
	IL-4 activates AR through enhanced expression of CBP/p300 and its histone acetyltransferase activity	[319]
	p300 modulates nuclear morphology in PCa and is required for androgen depletion independent activation of the AR	[320]
	p300 mediates STAT3 acetylation on Lys685, which mediates STAT3 dimerization and is reversible by type I HDAC	[321]
	CBP/p300 is a component of a transcriptional complex that regulates SRC-dependent hypoxia-induced expression of VEGF	[322]
	The downregulation of p300 inhibits PCa cell proliferation both at the basal level and on IL6 stimulation	[323]
	p300 mediates androgen-independent transactivation of the AR by IL6	[324]
	p300 and p300/CBP acetylate the AR at sites governing hormone-dependent transactivation	[325]
Tip60 (KAT5)	Negatively regulates the proliferation of LNCaP cells via the caspase 3-dependent apoptosis pathway	[326]
	Associated with resistance to X-ray irradiation	[327]
	Inhibition by TH1834 increases the effect of ionizing radiation in PC-3 and DU145 cells, induces apoptosis and increases unrepaired DNA damage	[328]
	Interacts with ER-β to regulate endogenous gene expression such as CXCL12 and cyclin D2	[329,330]
	KAT5 and KAT6B positively regulate cell proliferation through PI3K/AKT signaling	[331]
	Inhibition by NU9056 induces a decrease of AR, PSA, p21 and p53 levels in LNCaP cells, which might explain the increase of apoptosis and the decrease of proliferation	[332]
	Overexpression increases the acetylation of the AR and its localization in the nucleus and promotes cell proliferation	[333]
	Tip60 and β-catenin complexes regulate expression of metastasis suppressor gene KAI1	[334]
	A possible role for Tip60 in the molecular pathway leading to the development of androgen-independent PCa following long-term androgen deprivation therapy	[335]
	Tip60 and HDAC1 regulate AR activity through changes to the acetylation status of the receptor	[336]
MYST1 (KAT8)	Regulates androgen signaling in PCa cells	[337]
	Regulates NF-κB and AR functions during proliferation of PCa cells	[338]
	FOXP3 induces H4K16 acetylation and H3K4 trimethylation and activation of multiple genes by recruiting KAT8 and causing displacement of PLU-1	[339]
KDACs
Class I	Maspin induction is a critical epigenetic event altered by class I HDACs in the restoration of balance to delay proliferation and migration ability of PCa cells	[340]
HDAC1	KLF5 inhibits STAT3 activity and tumor metastasis in PCa by suppressing IGF1 transcription cooperatively with HDAC1	[341]
	Involved in E-cadherin expression in PCa cells	[342]
	Ubiquitination of the AR and HDAC1 may constitute an additional mechanism for regulating AR function; HDAC1 and MDM2 function co-operatively to reduce AR mediated transcription that is attenuated by the HAT activity of the AR co-activator Tip60	[343]
HDAC3	Genetic knockdown of either HDAC1 or HDAC3 can suppress expression of AR-regulated genes, recapitulating the effect of HDAC inhibitor treatment	[344]
HDAC4	Positive regulator of AR SUMOylation, revealing a deacetylase-independent mechanism of HDAC action in PCa cells	[345]
	Recruitment of HDAC4 by transcription factor YY1 represses HOXB13 to affect cell growth in AR-negative PCa	[346]
HDAC6	Synergistic interaction with MEK-inhibitors in CRPC cells	[347]
	Metastatic prostate cancer-associated p62 inhibits autophagy flux and promotes EMT by sustaining the level of HDAC6	[348]
	Regulates AR hypersensitivity and nuclear localization via modulating Hsp90 acetylation in CRPC	[349]
HDAC7	HDAC7 localizes to the mitochondrial inner membrane space of prostate epithelial cells and exhibits cytoplasmic relocalization in response to initiation of the apoptotic cascade, which highlights a link between HDACs, mitochondria, and programmed cell death	[350]
HDAC11	HDAC11 depletion is sufficient to cause cell death and to inhibit metabolic activity in PC-3 cells	[351]
SIRT1	Modulates the sensitivity of PCa cells to vesicular stomatitis virus oncolysis	[352]
	Mesenchymal stem cells overexpressing SIRT1 inhibit PCa growth by recruiting NK cells and macrophages	[353]
	Loss of miR-449a in ERG-associated PCa promotes the invasive phenotype by inducing SIRT1	[354]
	SIRT1 and LSD1 competitively regulate KU70 functions in DNA repair and mutation acquisition	[355]
	The silencing of SIRT1 gene in PC-3 cells suppresses the movement, migration, and invasion, possibly via reversing the EMT process	[356]
	Loss of Sirt1 promotes prostatic intraepithelial neoplasia, reduces mitophagy, and delays Park2 translocation to mitochondria	[226]
	Existence of SIRT1 and MPP8 crosstalk in E-cadherin gene silencing and EMT	[357]
	Regulation of histone H2A.Z expression is mediated by SIRT1 in PCa	[358]
	Enhances matrix metalloproteinase-2 expression and tumor cell invasion of PCa cells	[359]
	SIRT1 induces EMT by cooperating with EMT transcription factors and enhances PCa cell migration and metastasis	[360]
	Inhibition of cortactin and SIRT1 expression attenuates migration and invasion of DU145 cells	[361]
	Deacetylation of FOXO3 by SIRT1 or SIRT2 leads to SKP2-mediated FOXO3 ubiquitination and degradation	[201]
	Disruption of a SIRT1-dependent autophagy checkpoint in the prostate results in prostatic intraepithelial neoplasia lesion formation	[362]
	Inhibition of SIRT1 activity increases the chemosensitivity of androgen-refractory PCa cells	[363]
	SIRT1 inhibition at the activity level as well as via shRNA results in a significant inhibition in the growth and viability of human PCa cells; inhibition of SIRT1 causes an increase in FOXO1 acetylation and transcriptional activation in PCa cells	[364]
	SIRT1 inhibition causes a decrease in cell growth, cell viability and the colony formation ability and an increase in FOXO1 acetylation and subsequent transcriptional activation regardless of p53 status; SIRT1 inhibition results in an increase in senescence in PC-3-p53 (wild type p53) cells whereas it results in an increase in apoptosis in PC-3 (lack p53) cells	[365]
	Upregulation of SIRT1 expression may play an important role in promoting cell growth and chemoresistance in androgen-refractory PC-3 and DU145 cells	[366]
	Required for antagonist-induced transcriptional repression of androgen-responsive genes by the AR	[367]
	SIRT1 is a regulator of AR expression and function	[368]
	FOXO1 activity in PCa cells is inhibited by deacetylation by SIRT1	[369]
SIRT2	Dysregulation of SIRT2 and histone H3K18 acetylation pathways associates with adverse PCa outcomes	[370]
SIRT3	Transcriptional repression of SIRT3 potentiates mitochondrial aconitase activation to drive aggressive PCa to the bone	[371]
	SIRT3 and SIRT6 promote PCa progression by inhibiting necroptosis-mediated innate immune response	[372]
	Inhibits PCa metastasis through regulation of FOXO3A by suppressing Wnt/β-catenin pathway	[373]
	Inhibits PCa by destabilizing c-MYC through regulation of the PI3K/AKT pathway	[374]
	Inactivation of SIRT3 leads to elevated SKP2 acetylation, which leads to increased SKP2 stability through impairment of the CDH1-mediated proteolysis pathway resulting in increase of SKP2 oncogenic function; cells expressing an acetylation-mimetic mutant display enhanced cellular proliferation and tumorigenesis in vivo	[202]
SIRT4	Mitochondrial PAK6 inhibits PCa cell apoptosis via the PAK6-SIRT4-ANT2 complex	[375]
SIRT5	SIRT 5 regulates the proliferation, invasion, and migration of PCa cells through acetyl-CoA acetyltransferase 1	[376]
SIRT6	E2F1 enhances glycolysis through suppressing Sirt6 transcription in cancer cells	[377]
	Inhibition of SIRT6 reduces cell viability and increases sensitivity to chemotherapeutics	[378]
SIRT7	SIRT7 depletion inhibits cell proliferation and androgen-induced autophagy by suppressing the AR signaling in PCa	[379]
	Promotes PCa cell aggressiveness and chemoresistance	[380]
	SIRT7 inactivation reverses metastatic phenotypes	[381]