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Simple Summary Prostate cancer is a leading cause of cancer-related deaths among men, and novel therapies for advanced PCa are urgently needed. Cardiac glycosides are a group of attractive candidates for anticancer repurposing, but deslanoside has not been tested for a potential anticancer effect so far. This study aims to test the anticancer effect of deslanoside in PCa and investigate the underlying mechanisms. Deslanoside effectively inhibited colony formation and tumor growth in multiple prostate cancer cell lines. Such an inhibitory effect involved both the cell cycle arrest at G2/M and the induction of apoptosis. Deslanoside altered the expression of many genes, which belonged to various cancer-associated cellular processes and signaling pathways. Altered expression levels for 15 deslanoside-modulated genes correlate with recurrence-free survival or overall survival in PCa patients, some of which have not been implicated in cancer before. Therefore, deslanoside exerts anticancer activity in PCa cells by modulating gene expression. Abstract Prostate cancer (PCa) is a leading cause of cancer-related deaths among men worldwide, and novel therapies for advanced PCa are urgently needed. Cardiac glycosides represent an attractive group of candidates for anticancer repurposing, but the cardiac glycoside deslanoside has not been tested for potential anticancer activity so far. We found that deslanoside effectively inhibited colony formation in vitro and tumor growth in nude mice of PCa cell lines 22Rv1, PC-3, and DU 145. Such an anticancer activity was mediated by both the cell cycle arrest at G2/M and the induction of apoptosis, as demonstrated by different functional assays and the expression status of regulatory proteins of cell cycle and apoptosis in cultured cells. Moreover, deslanoside suppressed the invasion and migration of PCa cell lines. Genome-wide expression profiling and bioinformatic analyses revealed that 130 genes were either upregulated or downregulated by deslanoside in both 22Rv1 and PC-3 cell lines. These genes enriched multiple cellular processes, such as response to steroid hormones, regulation of lipid metabolism, epithelial cell proliferation and its regulation, and negative regulation of cell migration. They also enriched multiple signaling pathways, such as necroptosis, MAPK, NOD-like receptor, and focal adhesion. Survival analyses of the 130 genes in the TCGA PCa database revealed that 10 of the deslanoside-downregulated genes (ITG2B, CNIH2, FBF1, PABPC1L, MMP11, DUSP9, TMEM121, SOX18, CMPK2, and MAMDC4) inversely correlated, while one deslanoside-upregulated gene (RASD1) positively correlated, with disease-free survival in PCa patients. In addition, one deslanoside-downregulated gene (ENG) inversely correlated, while three upregulated genes (JUN, MXD1, and AQP3) positively correlated with overall survival in PCa patients. Some of the 15 genes have not been implicated in cancer before. These findings provide another candidate for repurposing cardiac glycosides for anticancer drugs. They also suggest that a diverse range of molecular events underlie deslanoside’s anticancer activity in PCa cells.

Simple Summary Molecular signatures predictive of recurrence-free survival (RFS) and castration resistance are critical for treatment decision-making in prostate cancer (PCa), but the robustness of current signatures is limited. This study aims to identify castration-resistant PCa (CRPC)-associated genes and develop robust RFS and CRPC signatures. Among 287 genes differentially expressed between localized CRPC and hormone-sensitive PCa (HSPC) samples, 6 genes constituted a signature (CRPC-derived prognosis signature, CRPCPS) that predicted RFS. Moreover, a 3-gene panel derived from the 6 CRPCPS genes was capable of distinguishing CRPC from HSPC. The CRPCPS predicted RFS in 5/9 cohorts in the multivariate analysis and maintained prognostic in patients stratified by tumor stage, Gleason score, and lymph node metastasis status. It also predicted overall survival and metastasis-free survival. Notably, the signature was validated in another six independent cohorts. These findings suggest that these two signatures could be robust tools for predicting RFS and CRPC in clinical practice. Abstract Molecular signatures predictive of recurrence-free survival (RFS) and castration resistance are critical for treatment decision-making in prostate cancer (PCa), but the robustness of current signatures is limited. Here, we applied the Robust Rank Aggregation (RRA) method to PCa transcriptome profiles and identified 287 genes differentially expressed between localized castration-resistant PCa (CRPC) and hormone-sensitive PCa (HSPC). Least absolute shrinkage and selection operator (LASSO) and stepwise Cox regression analyses of the 287 genes developed a 6-gene signature predictive of RFS in PCa. This signature included NPEPL1, VWF, LMO7, ALDH2, NUAK1, and TPT1, and was named CRPC-derived prognosis signature (CRPCPS). Interestingly, three of these 6 genes constituted another signature capable of distinguishing CRPC from HSPC. The CRPCPS predicted RFS in 5/9 cohorts in the multivariate analysis and remained valid in patients stratified by tumor stage, Gleason score, and lymph node status. The signature also predicted overall survival and metastasis-free survival. The signature’s robustness was demonstrated by the C-index (0.55–0.74) and the calibration plot in all nine cohorts and the 3-, 5-, and 8-year area under the receiver operating characteristic curve (0.67–0.77) in three cohorts. The nomogram analyses demonstrated CRPCPS’ clinical applicability. The CRPCPS thus appears useful for RFS prediction in PCa.

Breast cancer is a common malignancy, but the understanding of its cellular and molecular mechanisms is limited. ZFHX3, a transcription factor with many homeodomains and zinc fingers, suppresses prostatic carcinogenesis but promotes tumor growth of liver cancer cells. ZFHX3 regulates mammary epithelial cells&rsquo, proliferation and differentiation by interacting with estrogen and progesterone receptors, potent breast cancer regulators. However, whether ZFHX3 plays a role in breast carcinogenesis is unknown. Here, we found that ZFHX3 promoted the proliferation and tumor growth of breast cancer cells in culture and nude mice, and higher expression of ZFHX3 in human breast cancer specimens was associated with poorer prognosis. The knockdown of ZFHX3 in ZFHX3-high MCF-7 cells decreased, and ZFHX3 overexpression in ZFHX3-low T-47D cells increased the proportion of breast cancer stem cells (BCSCs) defined by mammosphere formation and the expression of CD44, CD24, and/or aldehyde dehydrogenase 1. Among several transcription factors that have been implicated in BCSCs, MYC and TBX3 were transcriptionally activated by ZFHX3 via promoter binding, as demonstrated by luciferase-reporter and ChIP assays. These findings suggest that ZFHX3 promotes breast cancer cells&rsquo, proliferation and tumor growth likely by enhancing BCSC features and upregulating MYC, TBX3, and others.

Simple Summary Breast cancer is a common malignancy, but the understanding of its cellular and molecular mechanisms is limited. The ZFHX3 transcription factor regulates mammary epithelial cells’ proliferation and differentiation by interacting with estrogen and progesterone receptors. Both these receptors play crucial roles in breast cancer development, but whether ZFHX3 also impacts breast cancer is unknown. In this study, the authors aim to determine if ZFHX3 promotes breast cancer cells’ proliferation and tumor growth and explore the underlying cellular and molecular mechanisms. Higher ZFHX3 expression is associated with worse patient survival in breast cancer, ZFHX3 promotes the proliferation and tumor growth of breast cancer cells, and several breast cancer stem cell factors appear to be involved in the role of ZFHX3 in breast cancer growth. The findings suggest that ZFHX3 is a novel oncogenic molecule promoting breast cancer development. Such a molecule could provide novel opportunities for the treatment of breast cancer. Abstract Breast cancer is a common malignancy, but the understanding of its cellular and molecular mechanisms is limited. ZFHX3, a transcription factor with many homeodomains and zinc fingers, suppresses prostatic carcinogenesis but promotes tumor growth of liver cancer cells. ZFHX3 regulates mammary epithelial cells’ proliferation and differentiation by interacting with estrogen and progesterone receptors, potent breast cancer regulators. However, whether ZFHX3 plays a role in breast carcinogenesis is unknown. Here, we found that ZFHX3 promoted the proliferation and tumor growth of breast cancer cells in culture and nude mice; and higher expression of ZFHX3 in human breast cancer specimens was associated with poorer prognosis. The knockdown of ZFHX3 in ZFHX3-high MCF-7 cells decreased, and ZFHX3 overexpression in ZFHX3-low T-47D cells increased the proportion of breast cancer stem cells (BCSCs) defined by mammosphere formation and the expression of CD44, CD24, and/or aldehyde dehydrogenase 1. Among several transcription factors that have been implicated in BCSCs, MYC and TBX3 were transcriptionally activated by ZFHX3 via promoter binding, as demonstrated by luciferase-reporter and ChIP assays. These findings suggest that ZFHX3 promotes breast cancer cells’ proliferation and tumor growth likely by enhancing BCSC features and upregulating MYC, TBX3, and others.

Androgen/androgen receptor (AR) signaling drives both the normal prostate development and prostatic carcinogenesis, and patients with advanced prostate cancer often develop resistance to androgen deprivation therapy. The transcription factor Kr&uuml, ppel-like factor 5 (KLF5) also regulates both normal and cancerous development of the prostate. In this study, we tested whether and how KLF5 plays a role in the function of AR signaling in prostate cancer cells. We found that KLF5 is upregulated by androgen depending on AR in LNCaP and C4-2B cells. Silencing KLF5, in turn, reduced AR transcriptional activity and inhibited androgen-induced cell proliferation and tumor growth in vitro and in vivo. Mechanistically, KLF5 occupied the promoter of AR, and silencing KLF5 repressed AR transcription. In addition, KLF5 and AR physically interacted with each other to regulate the expression of multiple genes (e.g., MYC, CCND1 and PSA) to promote cell proliferation. These findings indicate that, while transcriptionally upregulated by AR signaling, KLF5 also regulates the expression and transcriptional activity of AR in androgen-sensitive prostate cancer cells. The KLF5-AR interaction could provide a therapeutic opportunity for the treatment of prostate cancer.