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.

• Keywords
• SMARCD1, SMARCD3, SWI/SNF complex, prognostic marker, prostate cancer,
• MeSH
• Chromosomal Proteins, Non-Histone * genetics   metabolism   MeSH
• Immunohistochemistry MeSH
• Middle Aged MeSH
• Humans MeSH
• Neoplasm Recurrence, Local pathology   metabolism   genetics   MeSH
• Lymphatic Metastasis MeSH
• Biomarkers, Tumor * genetics   metabolism   MeSH
• Prostatic Neoplasms, Castration-Resistant pathology   genetics   metabolism   MeSH
• Prostatic Neoplasms * pathology   metabolism   genetics   MeSH
• Prognosis MeSH
• Aged MeSH
• Neoplasm Grading MeSH
• Transcription Factors genetics   metabolism   MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Chromosomal Proteins, Non-Histone * MeSH
• Biomarkers, Tumor * MeSH
• SMARCD1 protein, human MeSH Browser
• Transcription Factors MeSH

Previous studies have demonstrated an involvement of chromatin-remodelling SWI/SNF complexes in the development of prostate cancer, suggesting both tumor suppressor and oncogenic activities. SMARCD1/BAF60A, SMARCD2/BAF60B, and SMARCD3/BAF60C are mutually exclusive accessory subunits that confer functional specificity and are components of all known SWI/SNF subtypes. To assess the role of SWI/SNF in prostate tumorigenesis, we studied the functions and functional relations of the SMARCD family members. Performing RNA-seq in LnCAP cells grown in the presence or absence of dihydrotestosterone, we found that the SMARCD proteins are involved in the regulation of numerous hormone-dependent AR-driven genes. Moreover, we demonstrated that all SMARCD proteins can regulate AR-downstream targets in androgen-depleted cells, suggesting an involvement in the progression to castration-resistance. However, our approach also revealed a regulatory role for SMARCD proteins through antagonization of AR-signalling. We further demonstrated that the SMARCD proteins are involved in several important cellular processes such as the maintenance of cellular morphology and cytokinesis. Taken together, our findings suggest that the SMARCD proteins play an important, yet paradoxical, role in prostate carcinogenesis. Our approach also unmasked the complex interplay of paralogue SWI/SNF proteins that must be considered for the development of safe and efficient therapies targeting SWI/SNF.

• Keywords
• SMARCD1/BAF60A, SMARCD2/BAF60B, SMARCD3/BAF60C, SWI/SNF complex, chromatin-remodeling, prostate cancer,
• MeSH
• Receptors, Androgen * genetics   metabolism   MeSH
• Chromosomal Proteins, Non-Histone genetics   metabolism   MeSH
• Humans MeSH
• Prostatic Neoplasms * genetics   MeSH
• Gene Expression Regulation MeSH
• Chromatin Assembly and Disassembly genetics   MeSH
• Signal Transduction MeSH
• Transcription Factors metabolism   MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Receptors, Androgen * MeSH
• Chromosomal Proteins, Non-Histone MeSH
• SMARCD1 protein, human MeSH Browser
• Transcription Factors MeSH

Thousands of non-coding variants have been associated with increased risk of human diseases, yet the causal variants and their mechanisms-of-action remain obscure. In an integrative study combining massively parallel reporter assays (MPRA), expression analyses (eQTL, meQTL, PCHiC) and chromatin accessibility analyses in primary cells (caQTL), we investigate 1,039 variants associated with multiple myeloma (MM). We demonstrate that MM susceptibility is mediated by gene-regulatory changes in plasma cells and B-cells, and identify putative causal variants at six risk loci (SMARCD3, WAC, ELL2, CDCA7L, CEP120, and PREX1). Notably, three of these variants co-localize with significant plasma cell caQTLs, signaling the presence of causal activity at these precise genomic positions in an endogenous chromosomal context in vivo. Our results provide a systematic functional dissection of risk loci for a hematologic malignancy.

• MeSH
• Adaptor Proteins, Signal Transducing genetics   immunology   MeSH
• B-Lymphocytes immunology   pathology   MeSH
• Chromatin chemistry   immunology   MeSH
• Chromosomal Proteins, Non-Histone genetics   immunology   MeSH
• Genetic Predisposition to Disease * MeSH
• Risk Assessment MeSH
• DNA, Intergenic genetics   immunology   MeSH
• Humans MeSH
• Quantitative Trait Loci MeSH
• Multiple Myeloma drug therapy   genetics   immunology   pathology   MeSH
• Neoplasm Proteins genetics   immunology   MeSH
• Plasma Cells immunology   pathology   MeSH
• Polymorphism, Genetic MeSH
• Primary Cell Culture MeSH
• Cell Cycle Proteins genetics   immunology   MeSH
• Antineoplastic Combined Chemotherapy Protocols MeSH
• Gene Expression Regulation, Neoplastic MeSH
• Repressor Proteins genetics   immunology   MeSH
• Base Sequence MeSH
• Transcriptional Elongation Factors genetics   immunology   MeSH
• Inheritance Patterns MeSH
• Guanine Nucleotide Exchange Factors genetics   immunology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• Adaptor Proteins, Signal Transducing MeSH
• CDCA7L protein, human MeSH Browser
• CEP120 protein, human MeSH Browser
• Chromatin MeSH
• Chromosomal Proteins, Non-Histone MeSH
• ELL2 protein, human MeSH Browser
• DNA, Intergenic MeSH
• Neoplasm Proteins MeSH
• PREX1 protein, human MeSH Browser
• Cell Cycle Proteins MeSH
• Repressor Proteins MeSH
• SMARCD3 protein, human MeSH Browser
• Transcriptional Elongation Factors MeSH
• Guanine Nucleotide Exchange Factors MeSH
• WAC protein, human MeSH Browser