Background: Circular RNAs (circRNAs) are essential participants in the development and progression of various malignant tumors. Previous studies have shown that cell migration-inducing protein (CEMIP) accelerates prostate cancer (PCa) anoikis resistance (AR) by activating autophagy. This study focused on the effect of circCEMIP on PCa metastasis. Methods: This study gradually revealed the role of circ_0004585 in PCa anoikis resistance via quantitative real-time PCR (qRT-PCR) analysis, western blotting, pull-down assays, and dual fluorescence reporter assays. Results: Functionally, circ_0004585 promoted PCa cells invasion and metastasis both in vitro and in vivo. Mechanistically, circ_0004585 directly interacted with miR-1248 to upregulate target gene expression. Furthermore, target prediction and dual-luciferase reporter assays identified transmembrane 9 superfamily member 4 (TM9SF4) as a potential miR-1248 target. Pathway analysis revealed that TM9SF4 activated autophagy to promote PCa cells anoikis resistance via mTOR phosphorylation. Conclusions: These results demonstrated that circ_0004585 played an oncogenic role during PCa invasion and metastasis by targeting the miR-1248/TM9SF4 axis while providing new insight into therapeutic strategy development for metastatic PCa.

The survival of cancer cells after detaching from the extracellular matrix (ECM) is essential for the metastatic cascade. The programmed cell death after detachment is known as anoikis, acting as a metastasis barrier. However, the most aggressive cancer cells escape anoikis and other cell death patterns to initiate the metastatic cascade. This study revealed the role of cell migration-inducing protein (CEMIP) in autophagy modulation and anoikis resistance during ECM detachment. CEMIP amplification during ECM detachment resulted in protective autophagy induction via a mechanism dependent on the dissociation of the B-cell lymphoma-2 (Bcl-2)/Beclin1 complex. Additional investigation revealed that acting transcription factor 4 (ATF4) triggered CEMIP transcription and enhanced protein kinase C alpha (PKCα) membrane translocation, which regulated the serine70 phosphorylation of Bcl-2, while the subsequent dissociation of the Bcl-2/Beclin1 complex led to autophagy. Therefore, CEMIP antagonization attenuated metastasis formation in vivo. In conclusion, inhibiting CEMIP-mediated protective autophagy may provide a therapeutic strategy for metastatic prostate cancer (PCa). This study delineates a novel role of CEMIP in anoikis resistance and provides new insight into seeking therapeutic strategies for metastatic PCa.

Recent research has shown that ferroptosis, the iron-dependent accumulation of lipid peroxides that leads to cell death, suppresses cancer metastasis. However, the role of ferroptosis in prostate cancer metastasis has not been completely elucidated. In the current study, we identified the essential role of serum/glucocorticoid regulated kinase 2 (SGK2) in promoting prostate cancer metastasis by inhibiting ferroptosis. We found that the expression of SGK2 was higher in metastatic prostate cancer and predicted poor clinical outcomes. SGK2 knockdown inhibited the metastatic capacity of prostate cancer cells in vivo and in vitro, while SGK2 overexpression inhibited ferroptosis and facilitated prostate cancer metastasis by phosphorylating the Thr-24 and Ser-319 sites of forkhead box O1 (FOXO1). This process induced the translocation of FOXO1 from the nucleus to the cytoplasm, relieving the inhibitory effect of FOXO1 on glutathione peroxidase 4 (GPX4). These findings delineated a novel role of SGK2 in ferroptosis regulation of prostate cancer metastasis, identifying a new key pathway driving prostate cancer metastasis and potentially providing new treatment strategies for metastatic prostate cancer.

Abiraterone, a novel androgen synthesis inhibitor, has been approved for castration-resistant prostate cancer (CRPC) treatment. However, most patients eventually acquire resistance to this agent, and the underlying mechanisms related to this resistance remain largely unelucidated. Lysine acetyltransferase 2 A (KAT2A) has been reported to enhance transcriptional activity for certain histone or non-histone proteins through the acetylation and post-translational modification of the androgen receptor (AR). Therefore, we hypothesised that KAT2A might play a critical role in the resistance of prostate tumours to hormonal treatment. In this study, we found that KAT2A expression was increased in abiraterone-resistant prostate cancer C4-2 cells (C4-2-AbiR). Consistently, elevated expression of KAT2A was observed in patients with prostate cancer exhibiting high-grade disease or biochemical recurrence following radical prostatectomy, as well as in those with poor clinical survival outcomes. Moreover, KAT2A knockdown partially re-sensitised C4-2-AbiR cells to abiraterone, whereas KAT2A overexpression promoted abiraterone resistance in parental C4-2 cells. Consistent with this finding, KAT2A knockdown rescued abiraterone sensitivity and inhibited the proliferation of C4-2-AbiR cells in a mouse model. Mechanistically, KAT2A directly acetylated the hinge region of the AR, and induced AR translocation from the cytoplasm to the nucleus, resulting in increased transcriptional activity of the AR-targeted gene prostate specific antigen (PSA) leading to resistance to the inhibitory effect of abiraterone on proliferation. Taken together, our findings demonstrate a substantial role for KAT2A in the regulation of post-translational modifications in AR affecting CRPC development, suggesting that targeting KAT2A might be a potential strategy for CRPC treatment.

Background: Acquisition of the chemoresistance to docetaxel (DTX), a microtubule-targeting agent, has been a huge obstacle in treatment for metastatic castration-resistant prostate cancer (mCRPC). Recently, strategies targeting the mitosis error correction mechanism including chromosomal passenger complex (CPC) were reported to reverse the resistance to microtubule-targeting anticancer agents. Meanwhile, accumulating evidence indicated the important roles of circRNAs in DTX resistance of prostate cancer (PCa). However, whether circRNAs could regulate DTX chemosensitivity by affecting the mitosis error correction mechanism remains unclear. Methods: Expression patterns of circ_0004087 and BUB1 were determined through mining the public circRNA datasets and performing western blot and qRT-PCR assays. Agarose gel electrophoresis, Sanger sequencing, and RNase R treatment were conducted to examine the circular characteristics of circ_0004087. CircRNA pull-down, mass spectrometry analysis, Co-IP, and dual-luciferase reporter assays were performed to uncover the interaction among circ_0004087, SND1, and MYB. The effects of circ_0004087 and BUB1 on docetaxel-based chemotherapy were explored by flow cytometry and in vivo drug studies upon xenografted tumor model. Results: In the present study, we revealed the profound interaction between a novel circRNA, circ_0004087, and the mitosis error correction mechanism. Mechanistically, circ_0004087 binding with transcriptional coactivator SND1 could stimulate the transactivation of MYB and enhance the expression of downstream target BUB1. In turn, elevated BUB1 expression further recruited CPC to centromeres and guaranteed the error-free mitosis of PCa cells. Biologically, the overexpression of circ_0004087 conferred while the knockdown impaired DTX resistance in PCa cells. Conclusions: Our study uncovered the crucial role of circ_0004087/SND1/MYB/BUB1 axis in modulating the error mitosis correction mechanism and DTX chemoresistance, suggesting that circ_0004087 may serve as a valuable prognostic biomarker and a potential therapeutic target in DTX-resistant PCa patients.

Cells detached from the extracellular matrix (ECM) can trigger different modes of cell death, and the survival of ECM‐detached cells is one of the prerequisites for the metastatic cascade. Ferroptosis, a form of iron‐dependent programmed cell death, has recently been found to be involved in matrix‐detached cancer cells. However, the molecular mechanisms by which ECM‐detached cells escape ferroptosis are not fully understood. Here, we observed that cell migration‐inducing protein (CEMIP) upregulation facilitates ferroptosis resistance during ECM detachment by promoting cystine uptake in prostate cancer (PCa) cells. Meanwhile, silencing CEMIP causes it to lose its ability to promote cystine uptake and inhibit ferroptosis. Mechanistically, the interaction of CEMIP with inositol 1,4,5‐trisphosphate receptor type 3 (ITPR3) modulates calcium ion (Ca²⁺) leakage from the endoplasmic reticulum, activating calcium/calmodulin‐dependent protein kinase II (CaMKII), which further facilitates nuclear factor erythroid 2‐related factor 2 (NRF2) phosphorylation and nuclear localization, leading to elevated transcription of solute carrier family 7 member 11 (SLC7A11), a glutamate/cystine antiporter, in PCa cells. Our findings delineate a novel role of CEMIP in ferroptosis resistance during ECM detachment and provide new insights into therapeutic strategies for metastatic PCa.