Epigenetic and Epitranscriptomic Control in Prostate Cancer

Abstract

The initiation of prostate cancer has been long associated with DNA copy-number alterations, the loss of specific chromosomal regions and gene fusions, and driver mutations, especially those of the Androgen Receptor. Non-mutational events, particularly DNA and RNA epigenetic dysregulation, are emerging as key players in tumorigenesis. In this review we summarize the molecular changes linked to epigenetic and epitranscriptomic dysregulation in prostate cancer and the role that alterations to DNA and RNA modifications play in the initiation and progression of prostate cancer.

Keywords: DNA methylation; RNA modifications; epigenetics; epitranscriptomics; histone modifications; novel therapeutics; prostate cancer.

Figure 1

Writers, readers and erasers involved in PCa. Thick arrows indicate over- (red) or under-expression (blue) of the indicated proteins in PCa. Red arrows with flat heads indicate inhibitor compounds under clinical trial against the designated proteins. Writers: KMT1A, KMT1B and KMT1E tri-methylate H3K9; SMYD3 di- and methylates H3K4; PRMT5 methylates H4R3; NSD2 di-methylates H3K36. Erasers: LSD1 demethylates H3K9 and H3K4; KDM5B mono, di- and tri-demethylates H3K4; KDM5B and KDM5C di- and tri-demethylate H3K4. Readers: BRD-containing proteins.

Figure 2

(A) Schematic overview of writers, readers and erasers of m⁶A methylation. Green ellipses represent writers. Blue ellipses represent regulators of the writer complex. Red ellipses represent erasers. Yellow ellipses represent readers. Orange circles represent m⁶A methylation mark. (B) Relevant m⁶A modifiers in PCa control. Thick arrows indicate over- (red) or under-expression (blue) of the indicated proteins in PCa. Increased or decreased expression of writers, erasers or readers leads to increased m⁶A deposition, which in turn regulates the fate of the indicated mRNAs and lncRNAs, modulating cellular processes: proliferation, apoptosis, adhesion, migration or invasion. Red arrows with flat heads indicate METTL3 inhibitor compounds.