Publications by Year: 2013

The androgen receptor (AR) is a transcription factor that drives the differentiation of prostate epithelium by regulating the expression of several hundred genes. Conversely, AR also plays a central role in prostate cancer (PCa) development, and it continues to be active in tumors that relapse after castration (castration-resistant prostate cancer, CRPC). The transactivation function of AR has been extensively studied, and AR can also function as a transcriptional repressor on a distinct set of genes, but the identity of the AR regulated genes that are critical for PCa remain unclear. Moreover, the extent to which AR acquires new functions during PCa development and progression remains to be determined. Recent studies have highlighted the central role of chromatin structure and histone posttranslational modifications in determining the spectrum of genes regulated by AR and all other transcription factors. While the role of DNA methylation in the epigenetic regulation of gene expression is well established, it is now appreciated that chromatin structure plays a central and dynamic role in the epigenetic regulation of gene expression. The focus of this review is on AR interactions with chromatin and how they regulate AR function in PCa development and progression.

The nonreceptor tyrosine kinase BMX (bone marrow tyrosine kinase gene on chromosome X) is abundant in various cell types and activated downstream of phosphatidylinositol-3 kinase (PI3K) and the kinase Src, but its substrates are unknown. Positional scanning peptide library screening revealed a marked preference for a priming phosphorylated tyrosine (pY) in the -1 position, indicating that BMX substrates may include multiple tyrosine kinases that are fully activated by pYpY sites in the kinase domain. BMX phosphorylated focal adhesion kinase (FAK) at Tyr⁵⁷⁷ subsequent to its Src-mediated phosphorylation at Tyr⁵⁷⁶. Loss of BMX by RNA interference or by genetic deletion in mouse embryonic fibroblasts (MEFs) markedly impaired FAK activity. Phosphorylation of the insulin receptor in the kinase domain at Tyr¹¹⁸⁹ and Tyr¹¹⁹⁰, as well as Tyr¹¹⁸⁵, and downstream phosphorylation of the kinase AKT at Thr³⁰⁸ were similarly impaired by BMX deficiency. However, insulin-induced phosphorylation of AKT at Ser⁴⁷³ was not impaired in Bmx knockout MEFs or liver tissue from Bmx knockout mice, which also showed increased insulin-stimulated glucose uptake, possibly because of decreased abundance of the phosphatase PHLPP (PH domain leucine-rich repeat protein phosphatase). Thus, by identifying the pYpY motif as a substrate for BMX, our findings suggest that BMX functions as a central regulator among multiple signaling pathways mediated by tyrosine kinases.

Low-grade prostate cancers (Gleason pattern 3, G3) detected on needle biopsies are generally viewed as indolent and suitable for conservative management with only interval repeat biopsies to monitor by watchful waiting. Higher grade tumors eventually emerge in 20% to 30% of these cases, but this process may only reflect incomplete sampling on the initial biopsy, such that it remains unknown whether G3 tumors generally progress to higher grades. In this study, we examined a series of adjacent G3 and Gleason pattern 4 (G4) tumors in radical prostatectomy specimens and found that all were concordant for the TMPRSS2:ERG gene fusion. Using hybrid-capture and deep sequencing in four fusion-positive cases, we found that adjacent laser-capture microdissected G3 and G4 tumors had identical TMPRSS2:ERG fusion breakpoints, confirming their clonal origin. Two of these G3 tumors had deletion of a single PTEN gene that was also deleted in the adjacent G4, while the G4 tumors in two cases had additional PTEN losses. These findings establish that a subset of G3 tumors progress to G4 or emerge from a common precursor. Further, they show that G3 tumors that progress to G4 may have molecular features distinguishing them from G3 tumors that do not progress. Thus, determining the spectrum of these genetic or epigenetic features may allow for the identification of G3 tumors on needle biopsies that are truly indolent versus those that have the potential to progress or that may already be associated with a G4 tumor that was not sampled at the initial biopsy, therefore, requiring more aggressive surveillance or intervention.