BACKGROUNDS: SWI/SNF complexes represent a family of multi-subunit chromatin remodelers that are affected by alterations in >20% of human tumors. While mutations of SWI/SNF genes are relatively uncommon in prostate cancer (PCa), the literature suggests that deregulation of various subunits plays a role in prostate tumorigenesis. To assess SWI/SNF functions in a clinical context, we studied the mutually exclusive, paralogue accessory subunits SMARCD1, SMARCD2, and SMARCD3 that are included in every known complex and are sought to confer specificity. METHODS: Performing immunohistochemistry (IHC), the protein levels of the SMARCD family members were measured using a tissue microarray (TMA) comprising malignant samples and matching healthy tissue of non-metastatic PCa patients (n = 168). Moreover, IHC was performed in castration-resistant tumors (n = 9) and lymph node metastases (n = 22). To assess their potential role as molecular biomarkers, SMARCD1 and SMARCD3 protein levels were correlated with clinical parameters such as T stage, Gleason score, biochemical recurrence, and progression-free survival. RESULTS: SMARCD1 protein levels in non-metastatic primary tumors, lymph node metastases, and castration-resistant samples were significantly higher than in benign tissues. Likewise, SMARCD3 protein expression was elevated in tumor tissue and especially lymph node metastases compared to benign samples. While SMARCD1 levels in primary tumors did not exhibit significant associations with any of the tested clinical parameters, SMARCD3 exhibited an inverse correlation with pre-operative PSA levels. Moreover, low SMARCD3 expression was associated with progression to metastasis. CONCLUSIONS: In congruence with previous literature, our results implicate that both SMARCD1 and SMARCD3 may exhibit relevant functions in the context of prostate tumorigenesis. Moreover, our approach suggests a potential role of SMARCD3 as a novel prognostic marker in clinically non-metastatic PCa.

2nd Department of Urology Centre of Postgraduate Medical Education Warsaw Poland

Center for Biomarker Research in Medicine Graz Styria Austria

Center for Cancer Research Medical University of Vienna Vienna Austria

Christian Doppler Laboratory for Applied Metabolomics Medical University Vienna Vienna Austria

Department for Experimental and Laboratory Animal Pathology Clinical Institute of Pathology Vienna Austria

Department of Pathology Medical University of Vienna Vienna Austria

Department of Urology 2nd Faculty of Medicine Charles University Prag Czech Republic

Department of Urology Comprehensive Cancer Center Medical University of Vienna Vienna Austria

Department of Urology University of Texas Southwestern Dallas Texas USA

Department of Urology Weill Cornell Medical College New York New York USA

Division of Urology Department of Special Surgery Jordan University Hospital The University of Jordan Amman Jordan

Karl Landsteiner Institute of Urology and Andrology Vienna Austria

Research Center for Evidence Medicine Urology Department Tabriz University of Medical Sciences Tabriz Iran

Unit of Laboratory Animal Pathology University of Veterinary Medicine Vienna Vienna Austria

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Hargreaves DC, Crabtree GR. ATP‐dependent chromatin remodeling: genetics, genomics and mechanisms. Cell Res. 2011;21(3):396‐420. PubMed PMC

Euskirchen GM, Auerbach RK, Davidov E, et al. Diverse roles and interactions of the SWI/SNF chromatin remodeling complex revealed using global approaches. PLoS Genet. 2011;7(3):e1002008. PubMed PMC

Euskirchen G, Auerbach RK, Snyder M. SWI/SNF chromatin‐remodeling factors: multiscale analyses and diverse functions. J Biol Chem. 2012;287(37):30897‐30905. PubMed PMC

Kadoch C, Hargreaves DC, Hodges C, et al. Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy. Nat Genet. 2013;45(6):592‐601. PubMed PMC

Shain AH, Pollack JR. The spectrum of SWI/SNF mutations, ubiquitous in human cancers. PLoS ONE. 2013;8(1):e55119. PubMed PMC

Lee RS, Roberts CWM. Linking the SWI/SNF complex to prostate cancer. Nat Genet. 2013;45(11):1268‐1269. PubMed

Sun A, Tawfik O, Gayed B, et al. Aberrant expression of SWI/SNF catalytic subunits BRG1/BRM is associated with tumor development and increased invasiveness in prostate cancers. Prostate. 2007;67(2):203‐213. PubMed

Heebøll S, Borre M, Ottosen PD, et al. SMARCC1 expression is upregulated in prostate cancer and positively correlated with tumour recurrence and dedifferentiation. Histol Histopathol. 2008;23(9):1069‐1076. PubMed

Balasubramaniam S, Comstock CES, Ertel A, et al. Aberrant BAF57 signaling facilitates prometastatic phenotypes. Clin Cancer Res. 2013;19(10):2657‐2667. PubMed PMC

Hansen RL, Heeboll S, Ottosen PD, Dyrskjøt L, Borre M. Smarcc1 expression: a significant predictor of disease‐specific survival in patients with clinically localized prostate cancer treated with no intention to cure. Scand J Urol Nephrol. 2011;45(2):91‐96. PubMed

Ertl IE, Brettner R, Kronabitter H, et al. The SMARCD family of SWI/SNF accessory proteins is involved in the transcriptional regulation of androgen receptor‐driven genes and plays a role in various essential processes of prostate cancer. Cells. 2022;12(1):124. PubMed PMC

Weissman B, Knudsen KE. Hijacking the chromatin remodeling machinery: impact of SWI/SNF perturbations in cancer. Cancer Res. 2009;69(21):8223‐8230. PubMed PMC

Michel BC, D'Avino AR, Cassel SH, et al. A non‐canonical SWI/SNF complex is a synthetic lethal target in cancers driven by BAF complex perturbation. Nat Cell Biol. 2018;20(12):1410‐1420. PubMed PMC

Cerami E, Gao J, Dogrusoz U, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2(5):401‐404. PubMed PMC

Gao J, Aksoy BA, Dogrusoz U, et al. u. a. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signaling. 2013;6(269):pl1. PubMed PMC

Humphrey PA. Gleason grading and prognostic factors in carcinoma of the prostate. Mod Pathol. 2004;17(3):292‐306. PubMed

Kim M, Yoo D, Pyo J, Cho W. Clinicopathological significances of positive surgical resection margin after radical prostatectomy for prostatic cancers: a meta‐analysis. Medicina. 2022;58(9):1251. PubMed PMC

Shahabi A, Satkunasivam R, Gill IS, et al. Predictors of time to biochemical recurrence in a radical prostatectomy cohort within the PSA‐era. Can Urol Assoc J. 2016;10(1‐2):17. PubMed PMC

Ro YK, Lee S, Jeong CW, Hong SK, Byun SS, Lee SE. Biochemical recurrence in Gleason score 7 prostate cancer in Korean men: significance of the primary Gleason grade. Korean J Urol. 2012;53(12):826‐829. PubMed PMC

Prensner JR, Iyer MK, Sahu A, et al. The long noncoding RNA SChLAP1 promotes aggressive prostate cancer and antagonizes the SWI/SNF complex. Nat Genet. 2013;45(11):1392‐1398. PubMed PMC

Mota STS, Vecchi L, Zóia MAP, et al. New insights into the role of polybromo‐1 in prostate cancer. Int J Mol Sci. 2019;20(12):2852. PubMed PMC

Cyrta J, Augspach A, De Filippo MR, et al. Role of specialized composition of SWI/SNF complexes in prostate cancer lineage plasticity. Nat Commun. 2020;11(1):5549. PubMed PMC

Xiao L, Parolia A, Qiao Y, et al. Targeting SWI/SNF ATPases in enhancer‐addicted prostate cancer. Nature. 2022;601(7893):434‐439. PubMed PMC

Shen H, Powers N, Saini N, et al. The SWI/SNF ATPase brm is a gatekeeper of proliferative control in prostate cancer. Cancer Res. 2008;68(24):10154‐10162. PubMed PMC

Dai Y, Ngo D, Jacob J, Forman LW, Faller DV. Prohibitin and the SWI/SNF ATPase subunit BRG1 are required for effective androgen antagonist‐mediated transcriptional repression of androgen receptor‐regulated genes. Carcinogenesis. 2008;29(9):1725‐1733. PubMed PMC

Sun D, Lee YS, Malhotra A, et al. miR‐99 family of microRNAs suppresses the expression of prostate specific antigen and prostate cancer cell proliferation. Cancer Res. 2011;71(4):1313‐1324. PubMed PMC

Luke MC, Coffey DS. Human androgen receptor binding to the androgen response element of prostate specific antigen. J Androl. 1994;15(1):41‐51. PubMed

Li R, Wheeler T, Dai H, Frolov A, Thompson T, Ayala G. High level of androgen receptor is associated with aggressive clinicopathologic features and decreased biochemical recurrence‐free survival in prostate: cancer patients treated with radical prostatectomy. Am J Surg Pathol. 2004;28(7):928‐934. PubMed

Henshall SM, Quinn DI, Lee CS, et al. Altered expression of androgen receptor in the malignant epithelium and adjacent stroma is associated with early relapse in prostate cancer. Cancer Res. 2001;61(2):423‐427. PubMed

Hashmi AA, Mudassir G, Irfan M, et al. Prognostic significance of high androgen receptor expression in prostatic acinar adenocarcinoma. Asian Pac J Cancer Prev. 2019;20(3):893‐896. PubMed PMC

Arora K, Barbieri CE. Molecular subtypes of prostate cancer. Curr Oncol Rep. 2018;20(8):58. PubMed

Bahmad HF, Jalloul M, Azar J, et al. Tumor microenvironment in prostate cancer: toward identification of novel molecular biomarkers for diagnosis, prognosis, and therapy development. Front Genet. 2021;12. 10.3389/fgene.2021.652747 PubMed DOI PMC

Zong S, Gao J. Identifying the tumor immune microenvironment‐associated prognostic genes for prostate cancer. Discov Oncol. 2024;15(1):42. PubMed PMC

Sun X, Wang L, Li H, et al. Identification of microenvironment related potential biomarkers of biochemical recurrence at 3 years after prostatectomy in prostate adenocarcinoma. Aging. 2021;13(12):16024‐16042. PubMed PMC