SUMMARY While chromosomal rearrangements fusing the androgen-regulated gene TMPRSS2 to the oncogenic ETS transcription factor ERG occur in approximately 50% of prostate cancers, how the fusion products regulate prostate cancer remains unclear. Using chromatin immunoprecipitation coupled with massively parallel sequencing (ChIP-Seq), we found that ERG disrupts androgen receptor (AR) signaling by inhibiting AR expression, binding to and inhibiting AR activity at gene-specific loci, and inducing repressive epigenetic programs via direct activation of the H3K27 methyltransferase EZH2, a Polycomb group protein. These findings provide a working model in which TMPRSS2-ERG plays a critical role in cancer progression by disrupting lineage-specific differentiation of the prostate and potentiating the EZH2-mediated de-differentiation program.

Summary The lateral hypothalamic area (LHA) acts in concert with the ventral tegmental area (VTA) and other components of the mesolimbic dopamine (DA) system to control motivation, including the incentive to feed. The anorexigenic hormone, leptin, modulates the mesolimbic DA system, although the mechanisms underlying this control have remained incompletely understood. We show that leptin directly regulates a population of leptin receptor (LepRb)-expressing inhibitory neurons in the LHA, and that leptin action via these LHA LepRb neurons decreases feeding and body weight. Furthermore, these LHA LepRb neurons innervate the VTA, and leptin action on these neurons restores VTA expression of the rate-limiting enzyme in DA production along with mesolimbic DA content in leptin-deficient animals. Thus, these findings reveal that LHA LepRb neurons link anorexic leptin action to the mesolimbic DA system.

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The prevalence of obesity continues to increase at alarming rates throughout the world, fostering the rise in obesity-related comorbidities, such as diabetes and cardiovascular disease (1-3). Whereas body energy homeostasis is tightly regulated, only recently have we begun to understand the physiologic mechanisms that regulate feeding and body weight to effect this balance (4, 5). One important mediator of body energy homeostasis is leptin, which is produced by adipocytes as a signal of the repletion of body energy (fat) stores (6, 7). Leptin acts in the central nervous system to promote satiety and enable neuroendocrine energy expenditure (8 -14). The lack of leptin action due to mutations in leptin (e.g. ob/ob mice) or LepRb (e.g. db/db mice) or as a consequence of lowered fat stores results in increased appetite and an energy-sparing neuroendocrine starvation response that includes infertility and growth retardation (6, 10). In ob/ob and db/db animals, hyperphagia paired with decreased energy expenditure results in morbid obesity and a propensity to Type 2 diabetes (12). Conversely, in normal leptin-sensitive animals, high leptin levels tend to reduce appetite and permit neuroendocrine energy expenditure, and leptin administration decreases feeding and body weight while preserving metabolic energy utilization (10). The failure of elevated leptin levels to mediate weight loss in common forms of human obesity suggests the attenuation of leptin action ("leptin resistance") in obese states, as with diet-induced obesity in rodents (15-17). Potential mechanisms to explain this leptin resistance include alterations in leptin signaling, among others (18,19).Leptin binding activates the constitutively LepRb-associated Janus kinase (Jak) 3 2 tyrosine kinase to mediate tyrosine phosphorylation-dependent leptin signaling via several pathways (8, 20 -23). Phosphorylated LepRb Tyr 1138 recruits the latent transcription factor, signal transducer and activator of transcription (STAT) 3 to mediate its tyrosine phosphorylation (20,22,23). The tyrosine phosphorylation of STAT proteins, including STAT3, promotes their nuclear translocation and ability to mediate transcriptional regulation (24, 25); hence, STAT3 recruitment by LepRb Tyr 1138 mediates its activation. Phosphorylated Tyr 985 of LepRb binds SH2-containing tyrosine phosphatase-2 (SHP2; aka PTPN11), which participates in extracellular signal-regulated kinase (ERK) activation during leptin signaling in cultured cells (22,26). Tyr 985 additionally binds the suppressor of cytokine signaling (SOCS) 3, and contributes to the attenuation of LepRb signaling (22,26,27). LepRb-associated Jak2 may also mediate signals independently of LepRb tyrosine phosphorylation sites (8,22), in addition to providing a second, lower affinity binding site for SOCS3 (28,29 3 The abbreviations used are: Jak, Janus kinase; STAT, signal transducers and activators of transcription; SH2, Src homology domain 2; ERK, extracellular signal-regulated kinase; SOCS3, suppressor of cytokine signaling 3; RS...