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Review
. 2022 Aug 17:13:886594.
doi: 10.3389/fendo.2022.886594. eCollection 2022.

Lysine Acetyltransferases and Their Role in AR Signaling and Prostate Cancer

Bharti Jaiswal  1 , Akanksha Agarwal  2 , Ashish Gupta  2
Affiliations
Review

Lysine Acetyltransferases and Their Role in AR Signaling and Prostate Cancer

Bharti Jaiswal et al. Front Endocrinol (Lausanne). .

Abstract

The development and growth of a normal prostate gland, as well as its physiological functions, are regulated by the actions of androgens through androgen receptor (AR) signaling which drives multiple cellular processes including transcription, cellular proliferation, and apoptosis in prostate cells. Post-translational regulation of AR plays a vital role in directing its cellular activities via modulating its stability, nuclear localization, and transcriptional activity. Among various post-translational modifications (PTMs), acetylation is an essential PTM recognized in AR and is governed by the regulated actions of acetyltransferases and deacetyltransferases. Acetylation of AR has been identified as a critical step for its activation and depending on the site of acetylation, the intracellular dynamics and activity of the AR can be modulated. Various acetyltransferases such as CBP, p300, PCAF, TIP60, and ARD1 that are known to acetylate AR, may directly coactivate the AR transcriptional function or help to recruit additional coactivators to functionally regulate the transcriptional activity of the AR. Aberrant expression of acetyltransferases and their deregulated activities have been found to interfere with AR signaling and play a key role in development and progression of prostatic diseases, including prostate cancer (PCa). In this review, we summarized recent research advances aimed at understanding the role of various lysine acetyltransferases (KATs) in the regulation of AR activity at the level of post-translational modifications in normal prostate physiology, as well as in development and progression of PCa. Considering the critical importance of KATs in modulating AR activity in physiological and patho-physiological context, we further discussed the potential of targeting these enzymes as a therapeutic option to treat AR-related pathology in combination with hormonal therapy.

Keywords: GCN5; HBO1; P300; PCAF; TIP60; androgen receptor; lysine acetyltransferases; prostate cancer.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Schematic diagram showing domains of androgen receptor. NTD depicts N-terminal domain, DBD- DNA binding domain, LBD- ligand binding domain respectively. Hinge region connects NTD and DBD. AF-1 and AF-2 (activation function domain 1 and 2) are located within NTD and LBD region respectively. Nuclear localization signal (NLS) is present from 617-633 amino acids.
Figure 2
Figure 2
Schematic diagram depicting domains of Lysine acetyl transferases modulating androgen receptor. (A) Schematic diagram of lysine acetyl transferases (KATs) depicting their domain organization that interact and modulate androgen receptor activity. (B) Amino acids acetylated by different KAT proteins in AR p300/CBP, PCAF and TIP60 acetylate lysine residues 630, 632 and 633 while GCN5 acetylate lysine residue 630 situated within hinge domain, while ARD1 acetylate lysine 618 located in DBD region. Sites targeted for acetylation by HBO1 and MOF are still not been identified.
Figure 3
Figure 3
Modulation of AR by different KAT proteins. In presence of androgen ligands, AR which normally resides in the cytosol in a monomer form, translocated inside the nucleus. Ligand bound AR dimerize and binds at androgen response elements (AREs) in the target gene promoters/enhancers to modulate the transcription of targeted gene. KAT proteins ARD1, TIP60 and GCN5 can induce translocation of AR from cytosol into the nucleus. All of these KAT proteins, except HBO1 act as transcriptional coactivator of AR. HBO1 act as co-repressor of AR and inhibit AR signaling.
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