Heat shock protein 27 mediates repression of androgen receptor function by protein kinase D1 in prostate cancer cells

Abstract

We have previously shown that protein kinase D1 (PKD1), charter member of PKD protein family, is downregulated in advanced prostate cancer (PC) and influences androgen receptor (AR) function in PC cells. Other independent studies showed that serine 82 residue in heat shock protein 27 (Hsp27) undergoes substrate phosphorylation by PKD1 and is associated with nuclear transport of AR resulting in increased AR transcriptional activity. In this study, we show that PKD1 interacts and phosphorylates Hsp27 at Ser82 in PC cells, which is mediated by p38-dependent mitogen-activated protein kinase pathway and is necessary for PKD1 repression of AR transcriptional activity and androgen-dependent proliferation of PC cells. The study provides first in vivo evidence that Hsp27 is a mediator of repression of AR function by PKD1 in PC cells, thereby linking the data in the published literature.

Identification of Mutations, Expression Alterations and Fusion Transcripts by Next Generation RNAseq in Castration-Resistant Prostate Cancer Cell lines with Possible Clinical Relevance

“…PRKD1 (protein kinase D1) is also known as protein kinase C mu (atypical PKC), which is a serine/threonine kinase and can be activated by PKC, involving various functions including adhesion, cell motility, and cell proliferation. PKD1 can interact with androgen receptor (AR) and modulated AR function in prostate cancer [42][43][44]. In our project, PRKD1 was down-regulated in PC3 (expression level: 4.5) and DU145 (expression level: 5.4), compared with LNCaP (expression level: 100), showing that mRNA level was decreased in androgen-independent phenotype, which is similar to PRKACB above.…”

Non-androgen Signaling Pathways in Castration-Resistant Prostate Cancer

“…Additionally, overexpression of PKD1 along with E-cadherin results in the decrease of cancer phenotype [206]. PKD1 also shown to modulate the functions of AR in prostate cancer cells [206][207][208]. Overexpression or knockdown models of PKD1 in cell lines revealed that PKD1 negatively regulates the function of AR [208] through the modulation of Hsp27-mediated AR functions [207].…”

“…PKD1 also shown to modulate the functions of AR in prostate cancer cells [206][207][208]. Overexpression or knockdown models of PKD1 in cell lines revealed that PKD1 negatively regulates the function of AR [208] through the modulation of Hsp27-mediated AR functions [207]. Recently, we have identified that the PCa cell lines with low levels of PKD1 (C4-2 and E006AA cell lines) also have low levels of E-cadherin, and high levels of EMT markers like N-cadherin, snail, vimentin, MMP-2 and MMP-9 [209].…”

Protein Kinase D Signaling in Cancer

“…PKD1 complexes with the androgen receptor and affects its transcriptional activity [ 176 ] . It was also shown that PKD1-mediated phosphorylation of Hsp27 at S82 is necessary for the repression of the transcriptional activity of the androgen receptor and androgen-dependent proliferation of prostate cancer cells [ 177 ] . Only little is known about the involved mechanism by which PKD1 is silenced in prostate cancer, but it may be speculated that a similar epigenetic silencing occurs than observed for gastric and breast cancer.…”