Tumor suppressor role of RBM22 in prostate cancer acting as a dual-factor regulating alternative splicing and transcription of key oncogenic genes

J. Montero-Hidalgo A.; Saez-Martinez P.; Sarmento-Cabral A.; S. De la Rosa-Herencia A.; Sanchez-Sanchez R.; Gonzalez-Serrano T.; Gomez-Gomez E.; D. Gahete M.; M. Luque R.; M. Jimenez-Vacas J.

doi:10.1530/endoabs.83.ERCO1

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Endocrine Abstracts (2022) 83 ERCO1 | DOI: 10.1530/endoabs.83.ERCO1

EYES2022 ESE Young Endocrinologists and Scientists (EYES) 2022 Endocrine-related Cancer (11 abstracts)

Tumor suppressor role of RBM22 in prostate cancer acting as a dual-factor regulating alternative splicing and transcription of key oncogenic genes

Montero-Hidalgo A. J. ^1,2,3,4 , Saez-Martinez P. ^4,3,2,1 , Sarmento-Cabral A. ^4,3,2,1 , De la Rosa-Herencia A. S. ^1,2,3,4 , Sanchez-Sanchez R. ^5,3,1 , Gonzalez-Serrano T. ^5,3,1 , Gomez-Gomez E. ^6,3,1 , Gahete M. D. ^1,2,3,4 , Luque R. M. ^4,3,2,1 & Jimenez-Vacas J. M. ^4,3,2,1

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¹Maimonides Biomedical Research Institute of Cordoba (IMIBIC), GC-27 OncObesity and Metabolism; ²University of Cordoba, Department of Cell Biology, Physiology and Immunology; ³Reina Sofia University Hospital (HURS); ⁴CIBER Physiopathology of Obesity and Nutrition (CIBERobn); ⁵HURS/IMIBIC, Anatomical Pathology Service; ⁶HURS/IMIBIC, Urology Service

Background: Prostate cancer (PCa) is one the leading causes of cancer-related deaths among men in developed countries. Therefore, the identification of novel molecular targets for treatment is urgently needed to improve patients’ outcomes. In this scenario, our group has recently reported that elements of the cellular machinery controlling alternative-splicing processes might be used as potential novel therapeutic tools for PCa. In this context, although RBM22 has been identified as a key spliceosome component and transcription factor, playing an important role in different cancer-types, its role in PCa remains unknown.

Objectives: To evaluate the potential pathophysiological role of RBM22 in PCa.

Methods: RBM22 levels (mRNA and protein) were evaluated in 4 independent cohorts of patients and two preclinical mouse models (TRAMP/Hi-Myc). The functional (proliferation, migration, tumorsphere- and colony-formation) and molecular (RNA-seq, nCounter PanCancer Pathways Panel) consequences of RBM22 modulation were assessed in vitro (LNCaP, 22Rv1, and PC-3 cell lines) and in vivo (xenograft model).

Results: We found that RBM22 is downregulated (at mRNA and protein-levels) in PCa samples, and its levels are inversely associated with key clinical aggressiveness features (i.e. extraprostatic extension and perineural invasion). Consistently, a gradual reduction of RBM22 from control to prostatic-intraepithelial neoplasia, and then to poorly differentiated PCa was observed in samples from two transgenic PCa mouse models (TRAMP and Hi-Myc). Notably, overexpression of RBM22 in PCa cells decreased aggressiveness features in vitro, and tumor growth in vivo using a preclinical xenograft mouse model. These actions were associated with the dysregulation of the splicing of numerous genes, alteration of the activity of key oncogenic signalling pathways (e.g. cell-cycle progression), and to the downregulation of critical upstream regulators of cell-cycle (i.e. CDK1, CCND1 and EPAS1).

Conclusion: Altogether, our data demonstrate that RBM22 plays a critical functional role in the pathophysiology of PCa and invites to suggest that targeting negative regulators of RBM22 expression/activity could represent a novel potential therapeutic strategy to tackle this devastating pathology.