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 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 asso...

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Published inCell death discovery Vol. 9; no. 1; p. 48
Main Authors Guo, Kaixuan, Liu, Cheng, Shi, Juanyi, Lai, Cong, Gao, Ze, Luo, Jiawen, Li, Zhuohang, Tang, Zhuang, Li, Kuiqing, Xu, Kewei
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group UK 07.02.2023
Springer Nature B.V
Nature Publishing Group
Subjects
631/67/589/466
631/80/83/2359
AKT protein
Apoptosis
Biochemistry
Biomedical and Life Sciences
Cell Biology
Cell Cycle Analysis
Feedback
Life Sciences
Metastases
Metastasis
Post-translation
Prognosis
Prostate cancer
Stem Cells
Therapeutic targets
TOR protein
Ubiquitination
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Summary: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.
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ISSN:2058-7716
2058-7716
DOI:10.1038/s41420-023-01341-0