Targeting hyaluronan-mediated motility receptor (HMMR) enhances response to androgen receptor signalling inhibitors in prostate cancer

Josephine A. Hinneh; Joanna L. Gillis; Chui Yan Mah; Swati Irani; Raj K. Shrestha; Natalie K. Ryan; Enomoto Atsushi; Zeyad D. Nassar; David J. Lynn; Luke A. Selth; Masashi Kato; Margaret M. Centenera; Lisa M. Butler

doi:10.1038/s41416-023-02406-8

Targeting hyaluronan-mediated motility receptor (HMMR) enhances response to androgen receptor signalling inhibitors in prostate cancer

Josephine A. Hinneh, Joanna L. Gillis, Chui Yan Mah, Swati Irani, Raj K. Shrestha, Natalie K. Ryan, Enomoto Atsushi, Zeyad D. Nassar, David J. Lynn, Luke A. Selth, Masashi Kato, Margaret M. Centenera, Lisa M. Butler

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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.

Original language	English
Pages (from-to)	1350-1361
Number of pages	12
Journal	British Journal of Cancer
Volume	129
Issue number	8
Early online date	6 Sept 2023
DOIs	https://doi.org/10.1038/s41416-023-02406-8
Publication status	E-pub ahead of print - 6 Sept 2023

Keywords

Prostate cancer
Translational research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Hinneh, J. A., Gillis, J. L., Mah, C. Y., Irani, S., Shrestha, R. K., Ryan, N. K., Atsushi, E., Nassar, Z. D., Lynn, D. J., Selth, L. A., Kato, M., Centenera, M. M., & Butler, L. M. (2023). Targeting hyaluronan-mediated motility receptor (HMMR) enhances response to androgen receptor signalling inhibitors in prostate cancer. British Journal of Cancer, 129(8), 1350-1361. Advance online publication. https://doi.org/10.1038/s41416-023-02406-8

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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.",

keywords = "Prostate cancer, Translational research",

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.}",

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doi = "10.1038/s41416-023-02406-8",

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Hinneh, JA, Gillis, JL, Mah, CY, Irani, S, Shrestha, RK, Ryan, NK, Atsushi, E, Nassar, ZD, Lynn, DJ , Selth, LA, Kato, M, Centenera, MM & Butler, LM 2023, 'Targeting hyaluronan-mediated motility receptor (HMMR) enhances response to androgen receptor signalling inhibitors in prostate cancer', British Journal of Cancer, vol. 129, no. 8, pp. 1350-1361. https://doi.org/10.1038/s41416-023-02406-8

TY - JOUR

T1 - Targeting hyaluronan-mediated motility receptor (HMMR) enhances response to androgen receptor signalling inhibitors in prostate cancer

AU - Hinneh, Josephine A.

AU - Gillis, Joanna L.

AU - Mah, Chui Yan

AU - Irani, Swati

AU - Shrestha, Raj K.

AU - Ryan, Natalie K.

AU - Atsushi, Enomoto

AU - Nassar, Zeyad D.

AU - Lynn, David J.

AU - Selth, Luke A.

AU - Kato, Masashi

AU - Centenera, Margaret M.

AU - Butler, Lisa M.

PY - 2023/9/6

Y1 - 2023/9/6

N2 - 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.

AB - 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.

KW - Prostate cancer

KW - Translational research

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U2 - 10.1038/s41416-023-02406-8

DO - 10.1038/s41416-023-02406-8

M3 - Article

C2 - 37673961

AN - SCOPUS:85170245587

SN - 0007-0920

VL - 129

SP - 1350

EP - 1361

JO - British Journal of Cancer

JF - British Journal of Cancer

IS - 8

ER -

Targeting hyaluronan-mediated motility receptor (HMMR) enhances response to androgen receptor signalling inhibitors in prostate cancer

Abstract

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