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Cellular and Molecular Biology

MYB interacts with androgen receptor, sustains its ligand-independent activation and promotes castration resistance in prostate cancer

British Journal of Cancer volume 126, pages 1205–1214 (2022)Cite this article

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Abstract

Background

Aberrant activation of androgen receptor signalling following castration therapy is a common clinical observation in prostate cancer (PCa). Earlier, we demonstrated the role of MYB overexpression in androgen-depletion resistance and PCa aggressiveness. Here, we investigated MYB-androgen receptor (AR) crosstalk and its functional significance.

Methods

Interaction and co-localization of MYB and AR were examined by co-immunoprecipitation and immunofluorescence analyses, respectively. Protein levels were measured by immunoblot analysis and enzyme-linked immunosorbent assay. The role of MYB in ligand-independent AR transcriptional activity and combinatorial gene regulation was studied by promoter-reporter and chromatin immunoprecipitation assays. The functional significance of MYB in castration resistance was determined using an orthotopic mouse model.

Results

MYB and AR interact and co-localize in the PCa cells. MYB-overexpressing PCa cells retain AR in the nucleus even when cultured under androgen-deprived conditions. AR transcriptional activity is also sustained in MYB-overexpressing cells in the absence of androgens. MYB binds and promotes AR occupancy to the KLK3 promoter. MYB-overexpressing PCa cells exhibit greater tumorigenicity when implanted orthotopically and quickly regain growth following castration leading to shorter mice survival, compared to those carrying low-MYB-expressing prostate tumours.

Conclusions

Our findings reveal a novel MYB-AR crosstalk in PCa and establish its role in castration resistance.

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Fig. 1: MYB and AR interact and co-localize with each other in prostate cancer cells.
Fig. 2: MYB-overexpressing cells are able to retain AR in the nucleus under androgen-deprived conditions.
Fig. 3: Transcriptional activity of AR is increased in MYB-expressing prostate cancer cells and sustained under androgen-depleted conditions.
Fig. 4: MYB facilitates castration-resistant growth of PCa cells in the orthotopic mouse model.
Fig. 5: Mice carrying MYB-overexpressing tumours have poorer survival.

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Data availability

We confirm that all the data in this manuscript is original and we have access to the raw data files.

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Acknowledgements

We would like to acknowledge the support of veterinarian and vivarium staff in our animal studies.

Funding information

We would like to acknowledge the funding from NIH/NCI [R01CA224306, U01CA185490 (to APS) and R01CA204801, R01CA231925 (to SS)] and USAMCI (to APS and SS).

Author information

Author notes

  1. These authors contributed equally: Sanjeev Kumar Srivastava, Mohammad Aslam Khan.

Authors and Affiliations

  1. Department of Pathology, College of Medicine, University of South Alabama, Mobile, AL, 36617, USA

    Sanjeev Kumar Srivastava, Mohammad Aslam Khan, Shashi Anand, Haseeb Zubair, Sachin Kumar Deshmukh, Girijesh Kumar Patel, Seema Singh, James Elliot Carter & Ajay Pratap Singh

  2. Cancer Biology Program, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, 36604, USA

    Sanjeev Kumar Srivastava, Mohammad Aslam Khan, Shashi Anand, Haseeb Zubair, Sachin Kumar Deshmukh, Girijesh Kumar Patel, Seema Singh & Ajay Pratap Singh

  3. Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL, 36688, USA

    Seema Singh & Ajay Pratap Singh

  4. Bioimaging Core Facility, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, 36604, USA

    Joel Andrews

  5. Department of Mathematics and Statistics, University of South Alabama, Mobile, AL, 36688, USA

    Bin Wang

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Contributions

Conception and design: APS, SKS, MAK, SA, HZ and SS; development of methodology: APS, SKS, MAK, SA, HZ and SS; experiment and data generation: SKS, MAK, SA, HZ, SKD, GKP and JA; analysis and interpretation of data: APS, SKS, MAK, SA, HZ, SKD, JA, BW and JEC; writing original draft: SKS and APS; writing/reviewing and editing: MAK, APS, SKS, SA, SKD, HZ, GKP and JA; administrative and study supervision: APS and SS. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Ajay Pratap Singh.

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The authors declare no competing interests.

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The study involved no human subjects. Only the de-identified and archived human prostate cancer tissues were used under an exempt (category 4) protocol as determined by the University of South Alabama Institutional Review Board.

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Srivastava, S.K., Khan, M.A., Anand, S. et al. MYB interacts with androgen receptor, sustains its ligand-independent activation and promotes castration resistance in prostate cancer. Br J Cancer 126, 1205–1214 (2022). https://doi.org/10.1038/s41416-021-01641-1

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