The serine threonine kinase Akt1 has been implicated in the control of cellular metabolism, survival and growth. Herein, disruption of the ubiquitously expressed member of the Akt family of genes, Akt1, in the mouse, demonstrates a requirement for Akt1 in miRNA-mediated cellular apoptosis. The miR-17/20 cluster is known to inhibit breast cancer cellular proliferation through G1/S cell cycle arrest via binding to the cyclin D1 3'UTR. Here we show that miR-17/20 overexpression sensitizes cells to apoptosis induced by either Doxorubicin or UV irradiation in MCF-7 cells via Akt1. miR-17/20 mediates apoptosis via increased p53 expression which promotes Akt degradation. Akt1⁻/⁻ mammary epithelial cells which express Akt2 and Akt3 demonstrated increased apoptosis to DNA damaging agents. Akt1 deficiency abolished the miR-17/20-mediated apoptosis. These results demonstrated a novel pathway through which miR17/20 regulate p53 and Akt controlling breast cancer cell apoptosis.

Androgen-deprivation therapy (ADT) with newly developed antiandrogen enzalutamide (Enz) may increase the castration-resistant prostate cancer (CRPC) patients survival an extra 4.8 months. Yet eventually most patients may fail with development of Enz resistance. While recent clinical studies indicated that the increased expression of the androgen receptor (AR) splicing variant ARv7 might have key roles for the development of Enz resistance in CRPC, its detailed mechanism, especially its linkage to the circular RNAs (circRNAs), a form of non-coding RNA, however, remains unclear. Here we found from human clinical sample survey that circRNA17 (hsa_circ_0001427) has a lower expression in higher Gleason score PCa, and results from in vitro cell lines studies also revealed the lower expression in CRPC C4-2 Enz-resistant (EnzR-C4-2) cells compared to their parental Enz-sensitive (EnzS-C4-2) cells. Mechanism dissection indicated that suppressing circRNA17 in EnzS-C4-2 cells increased ARv7 expression that might then lead to increase the Enz resistance and cell invasion. Mechanism dissection demonstrated that Enz could suppress the circRNA17 expression at the transcriptional level via suppressing transcription of its host gene PDLIM5, and circRNA17 could regulate ARv7 expression via altering the expression of miR-181c-5p that involved the direct binding of miR-181c-5p to the 3'UTR of ARv7. Preclinical study using in vivo mouse model with xenografted EnzR-CWR22Rv1 cells revealed that adding circRNA17 or miRNA-181c-5p could suppress the EnzR-CWR22Rv1 cells growth. Together, results from these preclinical studies suggest that circRNA17 may function as suppressor to alter the Enz sensitivity and cell invasion in CRPC cells via altering the miR-181c-5p/ARv7 signaling and targeting this newly identified signaling may help in the development of a better therapy to further suppress the EnzR cell growth.

A majority of the patients with advanced prostate cancer initially respond to androgen deprivation therapy and enzalutamide therapy, but eventually enter the castration-resistant prostate cancer (CRPC) phase. Some studies have shown that the activation of other signalling pathways in CRPC cells replaces the function of the androgen receptor, as well as promotes cell metastasis and progression. However, the mechanisms underlying this side effect remain unclear. The present study aims to explore the continued progression of cells after enzalutamide resistance. Low expression of circRNA-UCK2 (circUCK2) was detected in enzalutamide-resistant (EnzR) cells. Moreover, miR-767-5p was found to be resistant to EnzR cells when the level of circUCK2 is increased. The decrease in free miR-767-5p increases the expression of TET1 protein through the post-transcriptional regulation of mRNA, thereby inhibiting cell invasion and proliferation. Knocking down circUCK2 in enzalutamide-sensitive cells reduces the concentration of TET1, thereby increasing cell invasion and proliferation. A preclinical study using in vivo mouse models also showed that a high expression of circUCK2 inhibited the EnzR cell growth. Thus, this study might aid in developing a novel therapy to better suppress the CRPC progression.

The miR-221/222 cluster has been demonstrated to function as oncomiR in human cancers. miR-221/222 promotes epithelial-to-mesenchymal transition (EMT) and confers tamoxifen resistance in breast cancer. However, the effects and mechanisms by which miR-221/222 regulates breast cancer aggressiveness remain unclear. Here we detected a much higher expression of miR-221/222 in highly invasive basal-like breast cancer (BLBC) cells than that in non-invasive luminal cells. A microRNA dataset from breast cancer patients indicated an elevated expression of miR-221/222 in BLBC subtype. S-phase entry of the cell cycle was associated with the induction of miR-221/222 expression. miRNA inhibitors specially targeting miR-221 or miR-222 both significantly suppressed cellular migration, invasion and G1/S transition of the cell cycle in BLBC cell types. Proteomic analysis demonstrated the down-regulation of two tumor suppressor genes, suppressor of cytokine signaling 1 (SOCS1) and cyclin-dependent kinase inhibit 1B (CDKN1B), by miR-221/222. This is the first report to reveal miR-221/222 regulation of G1/S transition of the cell cycle. These findings demonstrate that miR-221/222 contribute to the aggressiveness in control of BLBC.

Castration-resistant prostate cancer (CRPC) is the latest stage of PCa, and there is almost no effective treatment available for the patients with CRPC when next-generation androgen deprivation therapy drugs, such as enzalutamide (ENZ), fail. The androgen receptor (AR) plays key roles in PCa and CRPC progression and drug resistance. Histone acetyltransferase 1 (HAT1) has recently been reported to be highly expressed in some tumors, such as lung carcinoma. However, what relationship between the AR and HAT1, and whether or how HAT1 plays roles in CRPC progression and drug resistance remain elusive. In the present study, we found that HAT1 is highly expressed in PCa cells, and the overexpression of HAT1 is linked with CRPC cell proliferation. Moreover, the HAT1 expression is positively correlated with the expression of AR, including both AR-FL (full-length) and AR-V7 (variant 7), which is mainly mediated by a bromodomain containing protein 4 (BRD4) -mediated pathway. Furthermore, knockdown of HAT1 can re-sensitize the response of CRPC cells to ENZ treatment in cells and mouse models. In addition, ascorbate was observed to decrease AR expression through downregulation of HAT1 expression. Collectively, our findings reveal a novel AR signaling regulation pathway in PCa and CRPC and suggest that HAT1 serves as a critical oncoprotein and an ideal target for the treatment of ENZ resistance in CRPC patients.

MicroRNA-1303 (miR-1303) is involved in the tumorigenesis and progression of several cancers, and yet the role of miR-1303 in prostate cancer (PCa) and its underlying mechanism are unknown. To explore this issue, the present study aimed to use PCa tissues, cell lines and a PCa-engrafted mouse model to determine the expression and roles of miR-1303 in PCa. Furthermore, a series of experiments were conducted to explore the underlying mechanisms of action of miR-1303 in PCa cells. miR-1303 was demonstrated to be highly expressed in PCa tissues and cell lines. The level of miR-1303 expression was closely associated with higher Gleason scores and a more developed tumor stage in patients with PCa, and patients with higher levels of miR-1303 displayed a reduced overall survival rate. miR-1303 overexpression promoted the proliferation, migration and invasion of PCa cells. In vivo experiments showed that miR-1303 inhibition suppressed the growth of PCa tumors in mice. Additionally, dickkopf Wnt signaling pathway inhibitor 3 (DKK3) was identified as a target of miR-1303. Knockdown of miR-1303 suppressed the proliferation, migration and invasion of PCa cells, increased DKK3 expression, and inhibited the activity of the Wnt/β-catenin pathway. In conclusion, miR-1303 may promote proliferation, migration and invasion of PCa cells through activating the Wnt/β-catenin pathway by regulating DKK3 expression. These results indicated that miR-1303 may be considered as a potential biomarker for PCa treatment.

Most patients with advanced prostate cancer (PCa) initially respond well to androgen deprivation therapy (ADT) with antiandrogens, but most of them eventually become resistant to ADT. Here, we found that the antiandrogen Enzalutamide-resistant (EnzR) PCa cells can be suppressed by hyper-physiological doses of the androgen DHT. Mechanism dissection indicates that while androgens/androgen receptor (AR) can decrease BCL-2 expression to induce cell death, yet they can also simultaneously increase anti-apoptosis BCL-XL protein expression via decreasing its potential E3 ubiquitin ligase, PARK2, through transcriptionally increasing the miR-493-3p expression to target PARK2. Thus, targeting the high dose DHT/AR/miR-493-3p/PARK2/BCL-XL signaling with BCL-XL-shRNA can increase high-dose-DHT effect to better suppress EnzR cell growth via increasing the autophagic cell death. A preclinical study using in vivo mouse model also validated that suppressing BCL-XL led to enhance high dose DHT effect to induce PCa cell death. The success of human clinical trials in the future may help us to develop a novel therapy using high dose androgens to better suppress CRPC progression.

Prostate cancer (PCa) is one of the most common types of tumors among males worldwide. However, the roles of long noncoding RNAs (lncRNAs) in PCa remain unclear. This study shows that lncRNA FAM83H-AS1 is upregulated in prostate adenocarcinoma, bladder urothelial carcinoma, and kidney renal papillary cell carcinoma samples. Androgen receptor (AR) signaling plays the most important role in PCa tumorigenesis and development. In this study, the results validate that AR signaling is involved in upregulating FAM83H-AS1 expression in PCa cells. Loss-of-function assays demonstrate that FAM83H-AS1 acts as an oncogene in PCa by modulating cell proliferation, cell cycle, and migration. Bioinformatics analysis demonstrates that FAM83H-AS1 is remarkably related to the regulation of the cell cycle and DNA replication through affecting multiple regulators related to these pathways, such as CCNE2. Mechanically, we found that FAM83H-AS1 plays its roles through sponging miR-15a to promote CCNE2 expression. These findings indicate that FAM83H-AS1 is a novel diagnostic and therapeutic marker for PCa.

Androgen deprivation therapy (ADT) is a gold standard treatment for advanced PCa. However, most patients eventually develop the castration-resistant prostate cancer (CRPC) that progresses rapidly despite ongoing systemic androgen deprivation. While early studies indicated that high physiological doses of androgens might suppress rather than promote PCa cell growth in some selective CRPC patients, the exact mechanism of this opposite effect remains unclear. Here we found that Enzalutamide-resistant (EnzR) CRPC cells can be suppressed by the high-dose-androgen (dihydrotestosterone, DHT). Mechanism dissection suggested that a high-dose-DHT can suppress the circular RNA-BCL2 (circRNA-BCL2) expression via transcriptional regulation of its host gene BCL2. The suppressed circRNA-BCL2 can then alter the expression of miRNA-198 to modulate the AMBRA1 expression via direct binding to the 3'UTR of AMBRA1 mRNA. The consequences of high-dose-DHT suppressed circRNA-BCL2/miRNA-198/AMBRA1 signaling likely result in induction of the autophagic cell death to suppress the EnzR CRPC cell growth. Preclinical studies using in vivo xenograft mouse models also demonstrated that AMBRA1-shRNA to suppress the autophagic cell death can weaken the effect of high-dose-DHT on EnzR CRPC tumors. Together, these in vitro and in vivo data provide new insights for understanding the mechanisms underlying high-dose-DHT suppression of the EnzR CRPC cell growth, supporting a potential therapy using high-dose-androgens to suppress CRPC progression in the future.