@article{a120b4584e8344faaebe786d15f81825,
title = "Targeting hyaluronan-mediated motility receptor (HMMR) enhances response to androgen receptor signalling inhibitors in prostate cancer",
abstract = "Background: Resistance to androgen receptor signalling inhibitors (ARSIs) represents a major clinical challenge in prostate cancer. We previously demonstrated that the ARSI enzalutamide inhibits only a subset of all AR-regulated genes, and hypothesise that the unaffected gene networks represent potential targets for therapeutic intervention. This study identified the hyaluronan-mediated motility receptor (HMMR) as a survival factor in prostate cancer and investigated its potential as a co-target for overcoming resistance to ARSIs. Methods: RNA-seq, RT-qPCR and Western Blot were used to evaluate the regulation of HMMR by AR and ARSIs. HMMR inhibition was achieved via siRNA knockdown or pharmacological inhibition using 4-methylumbelliferone (4-MU) in prostate cancer cell lines, a mouse xenograft model and patient-derived explants (PDEs). Results: HMMR was an AR-regulated factor that was unaffected by ARSIs. Genetic (siRNA) or pharmacological (4-MU) inhibition of HMMR significantly suppressed growth and induced apoptosis in hormone-sensitive and enzalutamide-resistant models of prostate cancer. Mechanistically, 4-MU inhibited AR nuclear translocation, AR protein expression and subsequent downstream AR signalling. 4-MU enhanced the growth-suppressive effects of 3 different ARSIs in vitro and, in combination with enzalutamide, restricted proliferation of prostate cancer cells in vivo and in PDEs. Conclusion: Co-targeting HMMR and AR represents an effective strategy for improving response to ARSIs. [Figure not available: see fulltext.]",
author = "Hinneh, {Josephine A.} and Gillis, {Joanna L.} and Mah, {Chui Yan} and Swati Irani and Shrestha, {Raj K.} and Ryan, {Natalie K.} and Enomoto Atsushi and Nassar, {Zeyad D.} and Lynn, {David J.} and Selth, {Luke A.} and Masashi Kato and Centenera, {Margaret M.} and Butler, {Lisa M.}",
note = "Funding Information: The authors thank Jianling Xie, Madison Helm, Samira Khabbazi, Elizabeth Collis, Niwa Sawako, Makoto Kamei and Randall Grose for expert assistance with data generation. We acknowledge the SAHMRI ACRF Cellular Imaging and Cytometry Core Facility which is generously supported by the Australian Cancer Research Foundation, Detmold Hoopman Group and the Australian Government through the Zero Childhood Cancer Programme and the SAHMRI Light Microscopy and Laser Capture Core Facility for the support and assistance in this work. Animal experiments were carried out at the Nagoya University Graduate School of Medicine animal facility, Tsurumai campus. LNCaP-V16D and LNCaP-MR49F cells were a kind gift from Dr. Amina Zoubeidi (Vancouver Prostate Centre, Vancouver, Canada). The authors are grateful to the study participants, as well as the urologists, nurses, and histopathologists who assisted in the recruitment and collection of patient information and pathology reports through the Australian Prostate Cancer BioResource and the Nagoya University Hospital. Funding Information: 2. Gonit, M, Zhang, J, Salazar, MdA, Cui, H, Shatnawi, A, Trumbly, R & Ratnam, M 2011. NCBI Gene Expression Omnibus: GSE22483 {\textquoteleft}Hormone Depletion-Insensitivity of Prostate Cancer Cells Is Supported by the AR Without Binding to Classical Response Elements{\textquoteright}, Molecular Endocrinology, vol. 25, no. 4, pp. 621-634. https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE22483 Funding Information: This work was supported by grants from Cancer Australia (ID 1138766 to LMB, DJL and MMC; ID 2001432 to LAS and LMB; ID 2011672 to ZDN); the Movember Foundation and the Prostate Cancer Foundation of Australia through a Movember Revolutionary Team Award (MRTA-3 to LMB and LAS). JAH is supported by a Beacon of Enlightenment PhD Scholarship from the University of Adelaide. CYM is supported by an Early-Career Research Fellowship awarded by the Prostate Cancer Foundation of Australia. LAS and LMB are supported by Principal Cancer Research Fellowships (PRF2919 and PRF1117, respectively) awarded by the Cancer Council{\textquoteright}s Beat Cancer project on behalf of its donors, the State Government through the Department of Health and the Australian Government through the Medical Research Future Fund. Open Access funding enabled and organized by CAUL and its Member Institutions. Publisher Copyright: {\textcopyright} 2023, The Author(s).",
year = "2023",
month = oct,
day = "12",
doi = "10.1038/s41416-023-02406-8",
language = "English",
volume = "129",
pages = "1350--1361",
journal = "British Journal of Cancer",
issn = "0007-0920",
publisher = "Springer Nature",
number = "8",
}