Phosphorylation of histone H3 at threonine 11 establishes a novel chromatin mark for transcriptional regulation

Abstract

Posttranslational modifications of histones such as methylation, acetylation, and phosphorylation regulate chromatin structure and gene expression. Here we show that protein kinase C-related kinase 1 (PRK1) phosphorylates histone H3 at threonine 11 (H3T11) upon ligand-dependent recruitment to androgen receptor (AR) target genes. PRK1 is pivotal to AR function since PRK1 knockdown or inhibition impedes AR-dependent transcription. Blocking PRK1 function abrogates androgen-induced H3T11 phosphorylation, and inhibits androgen-induced demethylation of histone H3. Moreover, serine 5-phosphorylated RNA polymerase II is no longer observed at AR target promoters. Phosphorylation of H3T11 by PRK1 accelerates demethylation by the Jumonji C (JmjC) domain-containing protein JMJD2C. Thus, phosphorylation of H3T11 by PRK1 establishes a novel chromatin mark for gene activation, identifying PRK1 as a gatekeeper of ARdependent transcription. Importantly, levels of PRK1 and phosphorylated H3T11 correlate with Gleason scores of prostate carcinomas. Finally, inhibition of PRK1 blocks AR-induced tumour cell proliferation, making PRK1 a promising therapeutic target. Keywords PRK1; androgen receptor; histone phosphorylation; prostate cancerThe N-terminal tails of histones are subject to a plethora of posttranslational modifications such as methylation, acetylation, and phosphorylation by specific chromatin-modifying enzymes1. During gene expression, these modifications influence chromatin structure to facilitate the assembly of the RNA polymerase II transcription machinery1 , 2. Androgen receptor (AR)-dependent gene expression is characterized by changes in chromatin

Pleckstrin homology domain leucine-rich repeat protein phosphatases set the amplitude of receptor tyrosine kinase output

“…Indeed, molecular crosstalk is known to occur between histone phosphorylation and acetylation (18). Notably, phosphorylation at S10 and T11 of H3 leads to an increase in acetylation at K9 and K14 (19,48,49), as is consistent with our observation of coincident increases in phosphorylation on S10 and acetylation on K9 and K14 in cells lacking PHLPP1. The finding that PHLPP1 localizes at promoters whose transcription is suppressed by PHLPP but not at promoters whose transcription is not sensitive to PHLPP supports the possibility that PHLPP directly modifies histones on these promoters.…”

TET2 repression by androgen hormone regulates global hydroxymethylation status and prostate cancer progression

“…The epigenetic status of prostate cancer cells is modulated by AR binding and the subsequent recruitment of co-activators or co-repressors [14][15][16][17][18] . Acetylation, methylation, phosphorylation, ubiquitylation and ADP ribosylation of histones critically affect transcriptional regulation by ARs [19][20][21] . The main epigenetic mechanism that controls AR binding to DNA in prostate cancer is histone modification by histone acetyltransferases, histone methyltransferases and protein kinases at AR-binding sites (ARBSs) 20,21 .…”

“…Acetylation, methylation, phosphorylation, ubiquitylation and ADP ribosylation of histones critically affect transcriptional regulation by ARs [19][20][21] . The main epigenetic mechanism that controls AR binding to DNA in prostate cancer is histone modification by histone acetyltransferases, histone methyltransferases and protein kinases at AR-binding sites (ARBSs) 20,21 . Specific epigenetic codes modulate opening of chromatin to induce or repress the expression of proteinencoding genes and non-coding RNAs 11 .…”

Transcriptional Regulation of the Human Thromboxane A2 Receptor Gene by Wilms’ Tumour (WT)

“…Significantly in the context of PCa, through detailed mechanistic studies, we recently discovered that both the TPα and the TPβ isoforms directly interact with and regulate signalling by protein kinase C-related kinase/ protein kinase novel (PRK/PKN) (48), a family of 3 AGC kinases that act immediately downstream of phosphatidylinositol 3′kinases, and are strongly, yet differentially, implicated in several cancers (49)(50)(51) and in B-cell development (52). Indeed, in addition to acting as Rho GTPase effectors, activation of the PRKs (e.g., PRK1) in response to androgen receptor (AR) signalling within the prostate catalyses phosphorylation of histone (H)3 at Thr11 (H3pThr11) which, in turn, serves as a specific epigenetic marker, and gatekeeper, of androgen-induced chromatin remodelling and transcriptional activation (48,(53)(54)(55). Hence, owing to their ability to regulate RhoA-/C-mediated responses, including metastatic processes, combined with their epigenetic priming of tumour cells, members of the PRK family are key chemotherapeutic targets particularly in castrate-resistant prostate cancer, the metastatic lethal form of PCa that occurs following androgen deprivation therapy (53,55,56).…”

“…Indeed, in addition to acting as Rho GTPase effectors, activation of the PRKs (e.g., PRK1) in response to androgen receptor (AR) signalling within the prostate catalyses phosphorylation of histone (H)3 at Thr11 (H3pThr11) which, in turn, serves as a specific epigenetic marker, and gatekeeper, of androgen-induced chromatin remodelling and transcriptional activation (48,(53)(54)(55). Hence, owing to their ability to regulate RhoA-/C-mediated responses, including metastatic processes, combined with their epigenetic priming of tumour cells, members of the PRK family are key chemotherapeutic targets particularly in castrate-resistant prostate cancer, the metastatic lethal form of PCa that occurs following androgen deprivation therapy (53,55,56).…”