Biomolecules & Therapeutics
AR-mTOR-SRF Axis Regulates HMMR Expression in Human Prostate Cancer Cells
You Sun1, Zewu Li1 and Kyung Song1,2,3,4,*
1Department of Herbal Resources, Professional Graduate School of Oriental Medicine, Wonkwang University, Iksan 54538,
2Department of Pharmacy, College of Pharmacy, Wonkwang University, Iksan 54538,
3Institute of Pharmaceutical Research and Development, Wonkwang University, Iksan 54538,
4Integrated Omics Institute, Wonkwang University, Iksan 54538, Republic of Korea
Tel: +82-63-850-6817, Fax: +82-63-853-6821
Received: February 27, 2021; Revised: April 24, 2021; Accepted: May 16, 2021; Published online: June 8, 2021.
© The Korean Society of Applied Pharmacology. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
The elevated expression of the hyaluronan-mediated motility receptor (HMMR) is known to be highly associated with tumor progression in prostate cancer, but the molecular mechanisms underlying the regulation of HMMR expression remain unclear. Here, we report that mammalian target of rapamycin (mTOR) is a key regulator of HMMR expression, for which its kinase activity is required. Pharmacological inhibitors of mTOR, such as rapamycin and Torin2, markedly suppressed the mRNA level as well as the protein level of HMMR in LNCaP and PC-3 cells. Our data demonstrate that such regulation occurs at the transcription level. HMMR promoter reporter assays revealed that the transcription factor SRF is responsible for the mTOR-mediated transcriptional regulation of HMMR gene. Consistently, the suppression of HMMR expression by Torin2 was noticeably reversed by the overexpression of SRF. Moreover, our findings suggest that the SRF binding sites responsible for the transcriptional regulation of HMMR through the mTOR-SRF axis are located in HMMR promoter sequences carrying the first intron, downstream of the translational start site. Furthermore, the upregulation of HMMR by DHT was abolished by stimulation with rapamycin, prior to DHT treatment, suggesting that mTOR activity is required for the induction of HMMR expression by androgen. Collectively, our study provides new mechanistic insights into the role of mTOR/SRF/AR signaling in HMMR regulation in prostate cancer cells.
Keywords: HMMR, SRF, mTOR, Transcriptional regulation, Androgen receptor, Prostate cancer

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