bims-meproc 2025-07-06 papers

Issue of 2025–07–06
three papers selected by
Grigor Varuzhanyan, UCLA

Biotechnol Appl Biochem. 2025 Jul 01.

The Deubiquitinating Enzyme USP46 Abolishes Cell Survival of Prostate Cancer via Enhancing BECN1-Dependent Autophagy.

Yantao Yang, Hongwen Cao, Peng Sun, Yigeng Feng, Lei Chen, Renjie Gao.

Ubiquitin-specific peptidase 46 (USP46) is frequently underexpressed in several cancers. Its involvement and functional role in prostate cancer, however, are not well understood. This research focused on exploring how USP46 may suppress prostate cancer and its underlying mechanisms. USP46 mRNA levels in clinical prostate cancer samples were analyzed using the online The University of Alabama at Birmingham Cancer Data Analysis Portal (UALCAN) database. The expression of USP46 mRNA and protein was analyzed using RT-PCR and immunoblotting techniques. Cell proliferation, colony formation assays, and tumor growth curves were assessed by Cell Counting Kit-8 assay, crystal violet staining, and xenograft model, respectively. USP46's interaction with beclin 1 (BECN1) was evaluated using immunoprecipitation assays, whereas BECN1 knockdown was performed with siRNA. USP46 mRNA expression was significantly lower in prostate cancer cells compared to that in normal cells. Overexpression of USP46 significantly reduced cell proliferation, as shown by decreased cell viability and fewer colonies. Mechanistic studies demonstrated that USP46 interacted with and stabilized BECN1, supported by findings showing that USP46 overexpression increased BECN1 levels and delayed its degradation in prostate cancer cells treated with cycloheximide. Additionally, knockdown of BECN1 and inhibition of autophagy partially restored cell proliferation in USP46-overexpressing cells. USP46 interacts with and stabilizes BECN1, promoting autophagy and thereby suppressing prostate cancer cell proliferation. In conclusion, the current findings demonstrate that USP46 abolishes cell survival of prostate cancer via enhancing BECN1-dependent autophagy.

Keywords: USP46; autophagy; beclin 1 (BECN1); cell proliferation; prostate cancer

DOI: https://doi.org/10.1002/bab.70016

Cell Prolif. 2025 Jul 02. e70091

CDK12 Inactivation Attenuates Prostate Cancer Progression by Inhibiting BNIP3-Mediated Mitophagy.

Mengjun Huang, Hanqi Lei, Tongyu Tong, Hailin Zou, Binyuan Yan, Fei Cao, Yiting Wang, Qiliang Teng, Bin Xu, Juan Luo, Yupeng Guan, Shaohong Lai, Peng Li, Jun Pang.

Mitochondrial stress-induced mitophagy plays a critical role to maintain cellular homeostasis; however, in cancer cells, this process may also contribute to drug resistance. Our previous work identified CDK12 as a critical regulator of prostate cancer (PCa) cell survival under sustained enzalutamide exposure, though the precise mechanism remains to be elucidated. In this study, we hypothesize that CDK12 plays a key role in mitophagy regulation under mitochondrial stress, potentially modulating PCa cell resistance to enzalutamide, the first-line clinical medication in PCa therapy. Utilising multiple in vitro PCa cell models, we demonstrate that both CDK12 knockdown and pharmacological inhibition with THZ531 impaired mitophagy following treatment with enzalutamide and mitophagy inducer CCCP. Mechanistically, our finding reveal that CDK12 inhibition disrupts FOXO3-induced BNIP3 transcription, thereby preventing receptor-mediated mitophagy and sensitising PCa cells to enzalutamide. This study identifies the CDK12-FOXO3-BNIP3 pathway as a novel regulatory mechanism governing mitophagy under mitochondrial stress. Importantly, these results underscore CDK12's role in preserving mitochondrial function and promoting PCa cell survival during enzalutamide treatment. These findings highlight the therapeutic potential of targeting the CDK12-BNIP3-mitophagy axis in combination with antiandrogen therapies, offering a promising strategy to overcome drug resistance in PCa and improve clinical outcomes.

Keywords: BNIP3; CDK12; enzalutamide treatment; mitophagy; prostate cancer

DOI: https://doi.org/10.1111/cpr.70091

Cell Death Discov. 2025 Jul 03. 11(1): 306

Decoding MUC1 and AR axis in a radiation-induced neuroendocrine prostate cancer cell-subpopulation unveils novel therapeutic targets.

Catarina Macedo-Silva, Ângela Albuquerque-Castro, Iris Carriço, Joana Lencart, Isa Carneiro, Lucia Altucci, João Lobo, Vera Miranda-Gonçalves, Rui Henrique, Margareta P Correia, Carmen Jerónimo.

Despite the initial efficacy of radiotherapy (RT) in treating prostate adenocarcinoma (PCa), disease progression can lead to the emergence of neuroendocrine prostate cancer (NEPC) - a highly aggressive malignancy for which standard therapies are mostly ineffective. Although oncogenic MUC1-C is a leading driver of NEPC and of PCa lineage plasticity, its putative role in response to RT, including RT-induced neuroendocrine transdifferentiation (tNED), has not been explored. We thus aimed to explore the interplay between androgen receptor (AR) signaling and MUC1 in PCa progression to NEPC. Firstly, using a radioresistant PCa cell line (22Rv1-RR), we demonstrated that epigenetic suppression of AR signaling led to MUC1/MUC1-C upregulation, which seems to be activated through γSTAT3. MUC1 activation is positively associated with increased expression of neuroendocrine-related markers, including CD56, chromogranin A, synaptophysin, and INSM transcriptional repressor 1 (INSM1). In NEPC tissues and compared to prostate adenocarcinoma, MUC1 was upregulated and negatively correlated with AR, which was suppressed. Finally, proteomic analyses revealed that MUC1 activation upon RT selective pressure led to the acquisition of stemness features, induction of epithelial to mesenchymal transition, and enhancement of basal cell-like traits. Notably, MUC1 knockdown significantly boosted response to RT in both 22Rv1-RR and DU145 cell lines. Moreover, AR-induced overexpression in PC3 cell lines entailed MUC1 downregulation, resulting in attenuated neuroendocrine traits and radioresistance, as well as impaired cell migration and invasion capabilities. Collectively, these results highlight MUC1 as a promising radiosensitization target and may ultimately help overcome therapy resistance and NEPC progression.

DOI: https://doi.org/10.1038/s41420-025-02597-4