Accumulating data show that N6-methyladenosine (m⁶A) methyltransferase METTL3 and long noncoding RNA MALAT1 act pivotal roles in multiple malignancies including prostate cancer (PCa). However, the role and molecular mechanism underlying METTL3-mediated m⁶A modification of MALAT1 in PCa remain undocumented. The association of METTL3 and MALAT1 expression with clinicopathological characteristics and prognosis in patients with PCa was analyzed by quantitative real-time polymerase chain reaction (qRT-PCR), Western blot, and public The Cancer Genome Atlas (TCGA) dataset. The in vitro and in vivo experiments were executed to investigate the role of METTL3 in PCa. m⁶A dot blot, methylated RNA immunoprecipitation (MeRIP), RIP, and qRT-PCR assays were employed to observe METTL3-mediated m⁶A modification of MALAT1. The effects of METTL3 on MALAT1-mediated PI3K/AKT pathway were assessed by Western blot analysis. As a result, we found that METTL3 was significantly upregulated in PCa tissues and high expression of METTL3 was associated with Gleason score and tumor recurrence in patients with PCa. Knockdown of METTL3 markedly repressed growth and invasion of PCa cells in vitro and in vivo, whereas ectopic expression of METTL3 showed the opposite effects. Moreover, knockdown of METTL3 decreased the total m⁶A levels of PCa cells as well as the MALAT1 m⁶A levels, leading to reduced MALAT1 expression. Overexpression of MALAT1 reversed METTL3 knockdown-induced antitumor effects and PI3K/AKT signaling inactivation. MALAT1 harbored a positive correlation with METTL3 expression and tumor recurrence in PCa. In conclusion, our findings demonstrate that METTL3-mediated m⁶A modification of lncRNA MALAT1 promotes growth and invasion of PCa cells by activating PI3K/AKT signaling.

Tumor fatty acid (FA) metabolic plasticity plays a pivotal role in resistance to therapy and poses limitations to anticancer strategies. In this study, our aim is to uncover the role of acetate metabolism in neurodifferentiation (NED)-mediated castration-resistant prostate cancer (CRPC). We conducted analyses using LC-MS/MS on clinical prostate cancer tissue before and after hormone therapy. We established tumor xenograft mouse models, primary tumor cells, and human-derived organoids to detect the novel mechanism of NED and to identify potential therapies. The hormone therapy-induced upregulation of acetate metabolism was mediated by acyl-CoA synthetase short-chain family member 2 (ACSS2), which increased c-MYC expression for NED induction. Notably, combined treatment with an ACSS2 inhibitor and enzalutamide significantly reduced the xenograft tumor volume. Our findings uncovered the critical role of acetate metabolism in NED-mediated CRPC and suggest that ACSS2 inhibitors may represent a novel, low-toxicity strategy when combined with hormone therapy for treating patients with NED-mediated CRPC.

To evaluate noise hazard during holmium laser enucleation of the prostate (HoLEP), we designed a study to detect such a risk in this procedure. This study was conducted over a 12-month period on 223 patients with benign prostatic hyperplasia (BPH), 121 of whom underwent HoLEP while those remaining underwent transurethral resection of the prostate (TURP). A sound level meter was used to detect the exposure of surgeons to noise. The recordings used were in accordance with the standards set by the Occupational Safety and Health Administration (OSHA) and the United States E nvironmental Protection A gency . Moreover, each of the 43 surgeons participating in a BPH discussion conference answered the questionnaire on the influence of noise, and 33 surgeons in our department volunteered for blood pressure monitoring post-surgically. The sound level produced by a high-powered holmium laser emitter during HoLEP was 67.37 ± 0.13 dB, which was significantly higher than the sound heard during TURP (46.41 ± 0.29 dB, P < 0.01). The 65–70 dB noise during HoLEP was proved to be a safe level in accordance with the OSHA standards. However, this level was considerably greater than the stated 55 dB. Moreover, it exceeded the normal communication protective level of 60 dB. In the analysis of responses from the surgeons, the HoLEP group obtained an average score that reflected disturbance caused by the laser emitter and an increase in average systolic pressure relative to that in the TURP group. The noise level during HoLEP is within hearing conservation levels. However, the noise disturbs intrateam communication and concentration during surgery. Some surgeons may experience discomfort post-surgically, but no significant difference among the groups is indicated. The findings suggest that measures should be taken to address the noise caused by the laser emitter during HoLEP.

Metabolic rewiring is a starter for lineage plasticity, which is an important driver of prostate development, tumorigenesis and treatment resistance. Androgen-targeted therapies are central to prostate cancer (PCa) management, yet the mechanisms leading prostate development-particularly the metabolic signaling within basal cells during treatment-remain poorly understood. To fulfill this gap, we used multiple models to reveal the metabolic alterations in prostate basal cells. Our study reveals the role of the RBP4-STRA6 axis in modulating retinol metabolism and transporting retinol from adipocyte into prostate cells, contributing to prostate development and basal cell differentiation during androgen deprivation. Through multi-omics analyses, we demonstrate that RBP4-STRA6 axis dependent retinol metabolism is increased with androgen deprivation. Retinol metabolism rewiring is modulated by the androgen receptor (AR) and can regulate basal cell plasticity under androgen deprivation therapy (ADT). Retinol metabolism maintains prostate basal cell lineage plasticity during hormone therapy through the PPARγ signaling pathway, compensating for the AR signaling pathway inhibition by sustaining energy homeostasis and promoting basal cell differentiation. Notably, we identified a basal cell cluster (BC5) characterized by high Retinol metabolism and activated PPARγ signaling pathway, which plays a crucial role in basal-luminal differentiation and prostate growth. This study underscores the importance of RBP4-STRA6 dependent Retinol metabolism, mediating the crosstalk between adipocytes and prostate basal cells, in maintaining prostate development during hormone therapy and provides a foundation for future clinical interventions and diet strategies aimed at enhancing the sensitivity of androgen deprivation in prostate diseases.