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Medical castration that interferes with androgen receptor (AR) function is the principal treatment for advanced prostate cancer. However, clinical progression is universal, and tumors with ARindependent resistance mechanisms appear to be increasing in frequency. Consequently, there is an urgent need to develop new treatments targeting molecular pathways enriched in lethal prostate cancer. Lysine-specific demethylase 1 (LSD1) is a histone demethylase and an important regulator of gene expression. Here, we show that LSD1 promotes the survival of prostate cancer cells, including those that are castration-resistant, independently of its demethylase function and of the AR. Importantly, this effect is explained in part by activation of a lethal prostate cancer gene network in collaboration with LSD1's binding protein, ZNF217. Finally, that a small-molecule LSD1 inhibitor?SP-2509?blocks important demethylase-independent functions and suppresses castration-resistant prostate cancer cell viability demonstrates the potential of LSD1 inhibition in this disease. [ABSTRACT FROM AUTHOR]

Metabolic changes in cancer have been observed for almost a century. The mechanisms underlying these changes have begun to emerge from the recent studies implicating the tumor suppressor p53 in multiple metabolic pathways. The ability of p53 to regulate metabolism may also play important roles in the physiology of normal cells and organs. Here we demonstrate that p53 lowers bile acid (BA) levels under both normal and stressed conditions primarily through up-regulating expression of small heterodimer partner, a critical inhibitor of BA synthesis. Our results uncover a unique metabolic regulatory axis that unexpectedly couples p53 to BA homeostasis. Our results also warrant future studies to investigate a possible role of this axis in the tumor suppression by p53, because excessive quantities of BAs are cytotoxic and can cause liver damage and promote gastrointestinal cancers. [ABSTRACT FROM AUTHOR]

ASC-2, a multifunctional coactivator, forms a steady-state complex, named ASCOM (for ASC-2 COMplex), that contains the histone - H3-Iysine-4 (H3K4)-methyltransferase MLL3 or its paralogue MLL4. Somewhat surprisingly, given prior indications of redundancy between MLL3 and MLI4, targeted inactivation of the MLL3 H3K4-methylation activity in mice is found to result in ureter epithelial tumors. Interestingly, this phenotype is exacerbated in a p53+/- background and the tumorigenic cells are heavily immunostained for γH2AX. indicating a contribution of MLL3 to the DNA damage response pathway through p53. Consistent with the in vivo observations, and the demonstration of a direct interaction between p53 and ASCOM, cell-based assays have revealed that ASCOM, through ASC-2 and MLL3/4, acts as a p53 coactivator and is required for H3K4-trimethyation and expression of endogenous p53-target genes in response to the DNA damaging agent doxorubicin. In support of redundant functions for MLL3 and MLL4 for some events, siRNA-mediated down-regulation of both MLL3 and MLL4 is required to suppress doxorubicin-inducible expression of several p53-target genes. Importantly, this study identifies a specific H3K4 methytransferase complex, ASCOM, as a physiologically relevant coactivator for p53 and implicates ASCOM in the p53 tumor suppression pathway in vivo. [ABSTRACT FROM AUTHOR]