Although dysregulated HMMR is linked to prostate cancer (PCa) prognosis, the precise mechanisms remain unclear. Here, we sought to elucidate the role of HMMR in PCa progression as well as underlying mechanism. Herein, we found that upregulation of HMMR frequently observed in PCa samples and was associated with poor prognosis. Additionally, HMMR significantly promoted PCa proliferation and metastasis through gain- and loss-of function approaches in vitro and in vivo. Mechanistically, HMMR may interact with AURKA and elevated AURKA protein level through inhibiting ubiquitination-mediated degradation, which subsequently activated mTORC2/AKT pathway to ensure the reinforcement of PCa progression. Moreover, upregulated E2F1 caused from sustained activation of mTORC2/AKT pathway in turn function as transcription factor to promote HMMR transcription, thereby forming a positive feedback loop to trigger PCa progression. Importantly, administration of the mTOR inhibitor partially antagonised HMMR-mediated PCa progression in vivo. In summary, we not only reveal a novel possible post-translation mechanism mediated by HMMR involved in AURKA regulation, but also describe a positive feedback loop that contributes to PCa deterioration, suggesting HMMR may serve as a potential promising therapeutic target in PCa.

尽管失调的 HMMR 与前列腺癌 (PCa) 预后有关，但确切机制仍不清楚。在这里，我们试图阐明 HMMR 在 PCa 进展中的作用以及潜在机制。在此，我们发现在 PCa 样本中经常观察到 HMMR 的上调，并且与不良预后相关。此外，HMMR 通过体外和体内功能获得和丧失的方法显着促进 PCa 增殖和转移。从机制上讲，HMMR 可能通过抑制泛素化介导的降解与 AURKA 相互作用并升高 AURKA 蛋白水平，随后激活 mTORC2/AKT 通路以确保加强 PCa 进展。此外，由 mTORC2/AKT 通路持续激活引起的 E2F1 上调反过来作为转录因子促进 HMMR 转录，从而形成一个正反馈回路来触发 PCa 进展。重要的是，施用 mTOR 抑制剂可部分拮抗 HMMR 介导的体内 PCa 进展。总之，我们不仅揭示了一种新的可能由 HMMR 介导的参与 AURKA 调节的翻译后机制，而且还描​​述了导致 PCa 恶化的正反馈回路，表明 HMMR 可能作为 PCa 中潜在的有前途的治疗靶点。