Selected Articles from This Issue

Prostate cancer dormancy post-androgen deprivation therapy (ADT) is a commonly observed phenomenon that often leads to recurrence as castration-resistant prostate cancer (CRPC). To avoid recurrence of this lethal cancer and develop therapeutic targets for post-ADT dormant prostate cancer, it is vital to understand the mechanism of cellular entry into the dormant state. In their study, Kang and colleagues found that expression of B7-H4 was upregulated in post-castration dormant PDX models and in clinical post-ADT prostate cancer tissues. Transcriptomic analysis of neo-adjuvant hormone therapy treated patient samples verified a negative association between VTCN1 (B7-H4) expression and androgen receptor signaling targets KLK2, KLK3, and KLK4. Gene set enrichment analysis using VTCN1-expressing and non-expressing cells identified enrichment of extracellular matrix (ECM) interaction pathways in VTCN1-expressing cells. Accordingly, overexpression of B7-H4 diminished prostate cancer cell growth under androgen-deficient conditions in vitro, and delayed recurrence in castrated hosts in vivo. The authors also found that post-castration ECM in the PDX model presented with heightened levels of collagen. Taken together, this study presents B7-H4 as a potential target to manage ADT-induced dormancy and recurrent CRPC.Maternal embryonic leucine zipper kinase (MELK) has been identified as a highly upregulated therapeutic target in several cancers, and while MELK inhibitors have demonstrated promise in clinical trials, they have not been explored in esophageal squamous cell carcinoma (ESCC). Likewise, chronotherapeutic approaches to cancer have been minimally explored. To investigate the regulation of MELK expression and determine the efficacy of a chronotherapeutic approach to MELK inhibition, Zeng and colleagues performed RNA sequencing on mouse esophageal tissues that were collected intermittently throughout a 24-hour period. The sequencing revealed diurnal rhythms for MELK and circadian clock genes Bmal1, Clock, DBP, and REV-ERBα. Correspondingly, the authors treated mice bearing esophageal tumors with MELK inhibitor OTS167 in a rhythm-dependent manner and observed a decrease in tumor volume and weight. Assessment of OTS167 rhythmic dosing suggested that MELK inhibition has time-dependent effects on apoptosis and cell cycle arrest. Using publicly available transcriptomic data, the authors showed that MELK is associated with the dysregulation of core clock gene expression in ESCC and found that Bmal1 could transcriptionally regulate MELK, presenting a novel association between circadian rhythm and MELK expression in ESCC.Elevated intratumoral 17β-estradiol (E2) is a frequent occurrence in breast cancer, but how E2 is retained in cells and contributes to breast cancer progression has not been determined. To address these questions, Kim and Kraus treated human breast cancer cell lines with E2 for 20 to 40 minutes, then removed the hormone from the medium. Robust E2-dependent changes in gene expression (after hours) and cell proliferation (after days) were observed with continuous E2 treatment, as well as after a short treatment followed by removal of E2 from the medium. The sustained responses after hormone removal were due to E2 that was retained and accumulated in the cells by a protein called ASTER-B (GRAMD1B). ASTER-B is a cholesterol and steroid-binding protein, which is normally localized to the cytoplasm/endoplasmic reticulum. It is aberrantly localized to the nucleus of some breast cancer cells. Using a combination of GRAMD1B (ASTER-B) knockdown experiments and ectopic expression of FLAG-tagged ASTER-B mutants, the authors found that both steroid binding and nuclear mislocalization were required for intracellular E2 retention and gene regulation. Overall, this study provides insight into the mechanism of ASTER-B mediated E2 retention and indicates the potential clinical impact of ASTER-B localization.