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PTK6 activation at the membrane regulates epithelial-mesenchymal transition in prostate cancer.

ABSTRACT: The intracellular tyrosine kinase protein tyrosine kinase 6 (PTK6) lacks a membrane-targeting SH4 domain and localizes to the nuclei of normal prostate epithelial cells. However, PTK6 translocates from the nucleus to the cytoplasm in human prostate tumor cells. Here, we show that while PTK6 is located primarily within the cytoplasm, the pool of active PTK6 in prostate cancer cells localizes to membranes. Ectopic expression of membrane-targeted active PTK6 promoted epithelial-mesenchymal transition in part by enhancing activation of AKT, thereby stimulating cancer cell migration and metastases in xenograft models of prostate cancer. Conversely, siRNA-mediated silencing of endogenous PTK6 promoted an epithelial phenotype and impaired tumor xenograft growth. In mice, PTEN deficiency caused endogenous active PTK6 to localize at membranes in association with decreased E-cadherin expression. Active PTK6 was detected at membranes in some high-grade human prostate tumors, and PTK6 and E-cadherin expression levels were inversely correlated in human prostate cancers. In addition, high levels of PTK6 expression predicted poor prognosis in patients with prostate cancer. Our findings reveal novel functions for PTK6 in the pathophysiology of prostate cancer, and they define this kinase as a candidate therapeutic target. Cancer Res; 73(17); 5426-37. ©2013 AACR.

SUBMITTER: Zheng Y

PROVIDER: S-EPMC3766391 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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PTK6 activation at the membrane regulates epithelial-mesenchymal transition in prostate cancer.

Zheng Yu Y Wang Zebin Z Bie Wenjun W Brauer Patrick M PM Perez White Bethany E BE Li Jing J Nogueira Veronique V Raychaudhuri Pradip P Hay Nissim N Tonetti Debra A DA Macias Virgilia V Kajdacsy-Balla André A Tyner Angela L AL

Cancer research 20130715 17

The intracellular tyrosine kinase protein tyrosine kinase 6 (PTK6) lacks a membrane-targeting SH4 domain and localizes to the nuclei of normal prostate epithelial cells. However, PTK6 translocates from the nucleus to the cytoplasm in human prostate tumor cells. Here, we show that while PTK6 is located primarily within the cytoplasm, the pool of active PTK6 in prostate cancer cells localizes to membranes. Ectopic expression of membrane-targeted active PTK6 promoted epithelial-mesenchymal transiti ...[more]

PMID: 23856248

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Project description:BackgroundAndrogen deprivation therapies for the hormone-dependent stages of prostate cancer have become so effective that new forms of chemoresistant tumors are emerging in clinical practice, and require new targeted therapies in the metastatic setting. Yet there are important gaps in our understanding of the relevant transcriptional networks driving this process. Progression from localized to metastatic castration resistant prostate cancer (mCRPC) occurs as a result of accumulated resistance mechanisms that develop upon sustained androgen receptor (AR) suppression. Critical to this progression is the plastic nature by which prostate tumor cells transition from epithelial to mesenchymal states (EMT).MethodsHere, using prostate cancer cell lines with different AR composition, we systematically manipulated somatic proteins of the Bromodomain and ExtraTerminal (BET) family (BRD2, BRD3, and BRD4) to determine which BET proteins influence EMT. We used the TCGA repository to correlate the expression of individual BET genes with key EMT genes and determined biochemical recurrence in 414 patients and progression free survival in 488 patients.ResultsWe found that only BRD4-and not BRD2 or BRD3-regulates the expression of SNAI1 and SNAI2, and that the downregulation of these EMT transcription factors significantly increases E-cadherin expression. Furthermore, of the BET genes, only BRD4 correlates with survival outcomes in prostate cancer patients. Moreover, selective degradation of BRD4 protein with MZ1 ablates EMT (transcriptionally and morphologically) induced by TGFß signaling.ConclusionsMany relapsed/refractory tumors share a neuroendocrine transcriptional signature that had been relatively rare until highly successful antiandrogen drugs like abiraterone and enzalutamide came into widespread use. New therapeutic targets must therefore be developed. Our results identify key EMT genes regulated by BRD4, and offers a novel druggable target to treat mCRPC. BRD4-selective protein degraders offer a promising next generation approach to treat the emerging forms of chemoresistance in advanced prostate cancer.

Project description:The most frequent alteration in the prostate oncogenome is loss of chromosome (chr) 8p21 that has been associated with loss of NKX3.1 homeobox gene. Chr8p21 deletions increase significantly with tumor grade and are associated with poor prognosis in prostate cancer (PCa), suggesting critical involvement of this region in tumor progression. Recent studies suggest that apart from NKX3.1, this region harbors alternative tumor suppressors that are yet undefined. We proposed a novel, paradigm shifting hypothesis that this locus is associated with a miRNA gene cluster-miR-3622a/b- that plays a crucial suppressive role in PCa. Here we demonstrate the crucial role of miR-3622a in prostate cancer epithelial-to-mesenchymal transition (EMT). MicroRNA expression profiling in microdissected human PCa clinical tissues showed that miR-3622a expression is widely downregulated and is significantly correlated with poor survival outcome and tumor progression. To understand the functional significance of miR-3622a, knockdown and overexpression was performed using non-transformed prostate epithelial and PCa cell lines, respectively, followed by functional assays. Our data demonstrate that endogenous miR-3622a expression is vital to maintain the epithelial state of normal and untransformed prostate cells. miR-3622a expression inhibits EMT, progression and metastasis of PCa in vitro and in vivo. Further, we found that miR-3622a directly targets EMT effectors ZEB1 and SNAI2. In view of these data, we propose that frequent loss of miR-3622a at chr8p21 region leads to induction of EMT states that in turn, promotes PCa progression and metastasis. This study has potentially significant implications in the field of prostate cancer as it identifies an important miRNA component of a frequently lost chromosomal region with critical roles in prostate carcinogenesis which is a highly significant step towards understanding the mechanistic involvement of this locus. Also, our study indicates that miR-3622a is a novel PCa biomarker and potential drug target for developing therapeutic regimens against advanced PCa.

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PTK6 activation at the membrane regulates epithelial-mesenchymal transition in prostate cancer.

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PTK6 activation at the membrane regulates epithelial-mesenchymal transition in prostate cancer.

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