HMMR Promotes Prostate Cancer Proliferation and Metastasis via AURKA/mTORC2/E2F1 Positive Feedback Loop

Although dysregulated HMMR is linked to prostate cancer (PCa) prognosis, the precise mechanisms remain unclear. Here, we sought to elucidate the roles of HMMR in PCa progression as well as underlying mechanisms. Herein, we found that upregulated of HMMR frequently occurred in PCa samples and was corrected 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 interacted 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 of E2F1 caused from sustained activating 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 remarkably antagonized HMMR-mediated PCa progression in vivo. In summary, we not only reveal a novel post-translation mechanism mediated by HMMR involved in AURKA regulation, but also describe a positive feedback loop which contributes to PCa deterioration, suggesting HMMR may serve as a potential promising therapeutic target in PCa.