Histone deacetylase (HDAC) inhibitors have demonstrated clinical benefits in subtypes of hematological malignancies. However, the efficacy of HDAC inhibitors in solid tumors remains uncertain. This study takes breast cancer as a model to understand mechanisms accounting for limited response of HDAC inhibitors in solid tumors and to seek combination solutions. We discover that feedback activation of leukemia inhibitory factor receptor (LIFR) signaling in breast cancer limits the response to HDAC inhibition. Mechanistically, HDAC inhibition increases histone acetylation at the LIFR gene promoter, which recruits bromodomain protein BRD4, upregulates LIFR expression, and activates JAK1-STAT3 signaling. Importantly, JAK1 or BRD4 inhibition sensitizes breast cancer to HDAC inhibitors, implicating combination inhibition of HDAC with JAK1 or BRD4 as potential therapies for breast cancer.

AR (androgen receptor) signaling is crucial for the development and maintenance of the prostate as well as the initiation and progression of prostate cancer. Despite the AR's central role in prostate cancer progression, it is still unclear which AR-mediated processes drive the disease. Here, we identified 4 core autophagy genes: ATG4B, ATG4D, ULK1, and ULK2, in addition to the transcription factor TFEB, a master regulator of lysosomal biogenesis and function, as transcriptional targets of AR in prostate cancer. These findings were significant in light of our recent observation that androgens promoted prostate cancer cell growth in part through the induction of autophagy. Expression of these 5 genes was essential for maximal androgen-mediated autophagy and cell proliferation. In addition, expression of each of these 5 genes alone or in combination was sufficient to increase prostate cancer cell growth independent of AR activity. Further, bioinformatic analysis demonstrated that the expression of these genes correlated with disease progression in 3 separate clinical cohorts. Collectively, these findings demonstrate a functional role for increased autophagy in prostate cancer progression, provide a mechanism for how autophagy is augmented, and highlight the potential of targeting this process for the treatment of advanced prostate cancer.

Despite the known importance of androgen receptor (AR) signaling in prostate cancer (PCa), the processes downstream of AR that drive disease development and progression remain poorly understood. This knowledge gap has thus limited the ability to treat cancer. Here, it is demonstrated that androgens increase the metabolism of glutamine in PCa cells. This metabolism was required for maximal cell growth under conditions of serum starvation. Mechanistically, AR signaling promoted glutamine metabolism by increasing the expression of the glutamine transporters SLC1A4 and SLC1A5, genes commonly overexpressed in PCa. Correspondingly, gene expression signatures of AR activity correlated with SLC1A4 and SLC1A5 mRNA levels in clinical cohorts. Interestingly, MYC, a canonical oncogene in PCa and previously described master regulator of glutamine metabolism, was only a context-dependent regulator of SLC1A4 and SLC1A5 levels, being unable to regulate either transporter in phosphatase and tensin homolog (PTEN) wild-type cells. In contrast, rapamycin was able to decrease the androgen-mediated expression of SLC1A4 and SLC1A5 independent of PTEN status, indicating that mechanistic target of rapamycin complex 1 (mTORC1) was needed for maximal AR-mediated glutamine uptake and PCa cell growth. Taken together, these data indicate that three well-established oncogenic drivers (AR, MYC and mTOR) function by converging to collectively increase the expression of glutamine transporters, thereby promoting glutamine uptake and subsequent prostate cancer cell growth. Implications: AR, MYC and mTOR converge to increase glutamine uptake and metabolism in prostate cancer through increasing the levels of glutamine transporters.

Steroid hormones are lipophilic molecules produced in one cell that can travel great distances within the body to elicit biological effects in another cell. In the canonical pathway, steroid hormone binding to a nuclear receptor (NR), often in the cytoplasm, causes the receptor to undergo a conformational change and translocate to the nucleus, where it interacts with specific sequences of DNA to regulate transcription. In addition to the classical genomic mechanism of action, alternate mechanisms of steroid activity have emerged that involve rapid, non-genomic signaling. The distinction between these two major mechanisms of action lies in the subcellular location of the initiating steroid hormone action. Importantly, the mechanisms of action are not exclusive, in that each can affect the activity of the other. Here, we describe the different types of genomic and non-genomic steroid hormone signaling mechanisms and how they can influence one another to ultimately regulate biology. Further, we discuss the approaches being used to study the non-genomic signaling events and address important caveats to be considered when designing new experiments. Thus, this minireview can serve as an introduction to the diverse signaling mechanisms of steroid hormones and offers initial, experimental guidance to those entering the field.