Role Of SMARCA4 Research Articles

Delineation of a SMARCA4-specific competing endogenous RNA network and its function in hepatocellular carcinoma.

BACKGROUNDHepatocellular carcinoma (HCC) is a common malignancy worldwide, and the mortality rate continues to rise each year. SMARCA4 expression has been associated with poor prognosis in various types of cancer; however, the specific mechanism of action of SMARCA4 in HCC needs to be fully elucidated. AIMTo explore the specific mechanism of action of SMARCA4 in HCC.METHODSHerein, the expression level of SMARCA4 as well as its association with HCC prognosis were evaluated using transcriptome profiling and clinical data of 18 different types of cancer collected from The Cancer Genome Atlas database. Furthermore, SMARCA4-high and -low groups were identified. Thereafter, gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed to identify the function of SMARCA4, followed by construction of a SMARCA4-specific competing endogenous RNA (ceRNA) network using starBase database. The role of SMARCA4 in immunotherapy and its association with immune cells were assessed using correlation analysis.RESULTSIt was observed that SMARCA4 was overexpressed and negatively correlated with prognosis in HCC. Further, SMARCA4 expression was positively associated with tumor mutational burden, microsatellite stability, and immunotherapy efficacy. The SNHG3/THUMP3-AS1-miR-139-5p-SMARCA4 ceRNA network was established and could be assumed to serve as a stimulatory mechanism in HCC.CONCLUSIONThe findings of this study demonstrated that SMARCA4 plays a significant role in progression and immune infiltration in HCC. Moreover, a ceRNA network was detected, which was found to be correlated with poor prognosis in HCC. The findings of this study could contribute towards the identification of predictive markers for immunotherapy and a novel mechanism of action for HCC treatment.

Abstract 3277: SWI/SNF inactivation vulnerability

Abstract Genetic inactivation in specific SWI/SNF complex members induce sensitivity to the inhibition of KDM6A/UTX and KDM6B/JMJD3 in cancer. Despite the genetic inactivation of the tumor suppressor SMARCA4 is frequently found in cancer, there are no therapies that effectively target SMARCA4-deficient tumors. In our previous work, we reported that unlike the cells with activated MYC oncogene, cells with SMARCA4 inactivation are refractory to the histone deacetylase inhibitor, SAHA, leading to the aberrant accumulation of H3K27me3. In this context, SMARCA4 deficient cells showed an impaired transactivation and significantly reduced levels of the histone H3K27me3 specific demethylases, KDM6A/UTX and KDM6B/JMJD3, and their inhibition compromises cell viability specifically in SMARCA4 mutant cells. Furthermore, the in vivo administration of KDM6s inhibitor (GSK-J4) to mice orthotopically implanted with SMARCA4 mutant lung cancer cell lines or primary tumors of small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), showed a strong anti-tumor effect, highlighting the vulnerability of the SMARCA4 deficient tumors to KDM6s inhibition as a biomarker that could be exploited for treating SMARCA4-mutant cancer patients (Romero OA, Vilarrubi A, et al. SMARCA4 deficient tumors are vulnerable to KDM6A/UTX and KDM6B/JMJD3 blockade. Nat Comm 12, 4319, 2021). Considering our previous observations, and due to the biological role of SMARCA4 as a core component of the SWI/SNF chromatin-remodeling complex, whose members are genetically inactivated in approximately 20% of all human cancers, we wanted to determine the potential response to KDM6s inhibitors in a context of genetic alterations in genes encoding for the other subunits of this remodeling complex. For this propose, we have integrated state of the art technology like genome-wide chromatin modification analysis (ChIP-seq) and transcriptome analysis (RNA-seq), using human cancer cell lines and preclinical models of different cancer types with genetic inactivation at different SWI/SNF-complex members, including mouse models such as orthoxenografts, to design a personalized epigenetic treatment based on the genetic background. Our results showed that, like SMARCA4 deficient cells, specific mutations at some, but not all, SWI/SNF components induce refractoriness to SAHA, aberrant increase of H3K27me3 mark and sensitizes cancer cells to KDM6 inhibitor accompanied with significantly reduced levels of KDM6A and KDM6B expression. These results suggest a strong functional relationship between KDM6A/6B activity and the SWI/SNF-complex, in the control of gene expression and cancer development. These results will be of great value for the stratification of tumors according to their genetic background for tailored treatments, opening the possibility to use SWI/SNF mutations as potential biomarkers for personalized epigenetic-based therapeutics in cancer. Citation Format: Andrea Vilarrubi, Fernando Setien, Eva Pros, Pedro P. Medina, Antonio Gomez, Alberto Villanueva, Octavio A. Romero, Montse Sanchez-Cespedes. SWI/SNF inactivation vulnerability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3277.

SMARCA4 Depletion Induces Cisplatin Resistance by Activating YAP1-Mediated Epithelial-to-Mesenchymal Transition in Triple-Negative Breast Cancer.

Simple SummarySMARCA4 mutations were over-representative in cisplatin resistance and metastatic triple-negative breast cancer (TNBC). Additionally, SMARCA4 inactivation induced the mesenchymal-like subtype TNBC. The epithelial-to-mesenchymal transition and Hippo-YAP/TAZ pathways were activated in SMARCA4 inactivation samples of both SMARCA4 knockout cell lines and TNBC patients. In SMARCA4 knockout cells, the YAP1 inhibitor verteporfin suppressed YAP1 target genes. This study depicts the clinical importance of SMARCA4 depletion in TNBC and suggests YAP/TAZ as a novel target for cisplatin-resistant patients.The role of SMARCA4, an ATPase subunit of the SWI/SNF chromatin remodeling complex, in genomic organization is well studied in various cancer types. However, its oncogenic role and therapeutic implications are relatively unknown in triple-negative breast cancer (TNBC). We investigated the clinical implication and downstream regulation induced by SMARCA4 inactivation using large-scale genome and transcriptome profiles. Additionally, SMARCA4 was knocked out in MDA-MB-468 and MDA-MB-231 using CRISPR/Cas9 to identify gene regulation and a targetable pathway. First, we observed an increase in SMARCA4 mutations in cisplatin resistance and metastasis in TNBC patients. Its inactivation was associated with the mesenchymal-like (MSL) subtype. Gene expression analysis showed that the epithelial-to-mesenchymal transition (EMT) pathway was activated in SMARCA4-deficient patients. Next, the Hippo pathway was activated in the SMARCA4 inactivation group, as evidenced by the higher CTNNB1, TGF-β, and YAP1 oncogene signature scores. In SMARCA4 knockout cells, EMT was upregulated, and the cell line transcriptome changed from the SL to the MSL subtype. SMARCA4 knockout cells showed cisplatin resistance and Hippo-YAP/TAZ target gene activation. The YAP1 inhibitor verteporfin suppressed the expression of YAP1 target genes, and decreased cell viability and invasiveness on SMARCA4 knockout cells. SMARCA4 inactivation in TNBC endowed the resistance to cisplatin via EMT activation. The YAP1 inhibitor could become a novel strategy for patients with SMARCA4-inactivated TNBC.

Abstract IA21: Small cell carcinomas of the ovary: Strengths and weaknesses

Abstract Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare and very aggressive malignancy that occurs mostly in young women. We and others previously described SCCOHT as a SMARCA4-mutated monogenic disease and unraveled other important molecular features, including apparent universal loss of SMARCA2 through epigenetic silencing. Typically, SMARCA4 and SMARCA2 are redundant catalytic subunits of the SWI/SNF complex and loss of either will result in the overexpression of the other. However, SCCOHT is unique in having concomitant loss of both subunits with restoration of either leading to tumor suppression. Nonetheless, despite these advances in understanding the biology of SCCOHT, there are few effective treatment options and survival rates remain poor. In this presentation we will discuss the role of SMARCA4 and SMARCA2 on tumor growth. We will also present therapeutic options to manipulate SWI/SNF complex dependencies. We will present case histories of patients who have had positive responses to targeted therapies. We will also discuss responses to anti-PD1 immunotherapy and characterize the immune landscape of SCCOHT tumors using quantitative immunofluorescence and gene expression profiling. Unexpectedly for a low mutation burden cancer, the majority of the tumors demonstrated PD-L1 expression with strong associated T-cell infiltration. PD-L1 expression can be detected in both tumor and stromal cells, with macrophages being the most abundant PD-L1 positive cells in some tumors. These findings suggest that although SCCOHT are low-mutational-burden tumors, their immunogenic microenvironment that resembles the landscape of tumors that respond well to treatment with PD-1/PD-L1 blockade. Citation Format: Douglas A. Levine. Small cell carcinomas of the ovary: Strengths and weaknesses. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr IA21.

Identification of Driver Mutations in Rare Cancers: The Role of SMARCA4 in Small Cell Carcinoma of the Ovary, Hypercalcemic Type (SCCOHT).

Cancer is a complex genetic disease that can arise through the stepwise accumulation of mutations in oncogenes and tumor suppressor genes in a variety of different tissues. While the varied landscapes of mutations driving common cancer types such as lung, breast, and colorectal cancer have been comprehensively charted, the genetic underpinnings of many rare cancers remain poorly defined. Study of rare cancers faces unique methodological challenges, but collaborative enterprises that incorporate next generation sequencing, reach across disciplines (i.e., pathology, genetic epidemiology, genomics, functional biology, and preclinical modeling), engage advocacy groups, tumor registries, and clinical specialists are adding increasing resolution to the genomic landscapes of rare cancers. Here we describe the approaches and methods used to identify SMARCA4 mutations, which drive development of the rare ovarian cancer, small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), and point to the broader relevance of this paradigm for future research in rare cancers.

Case Report of a Patient With Speech Delay and Behavioral Disorders Associated with Neuroblastoma. Possible Role of SMARCA4

Pediatric cancers can occur within a context of predisposition syndromes, the exploration of which can in turn contribute to the detection of genes implicated in oncogenesis. For neuroblastoma, few associated malformative syndromes have been reported and these are only rarely characterized by genetic alterations identified to date. Here, we report the case of a girl with a delay in language acquisition and behavioral disorders associated with an adrenal neuroblastic tumor discovered at the age of 4 years.

Tissue-specific SMARCA4 binding at active and repressed regulatory elements during embryogenesis.

The SMARCA4 (also known as BRG1 in humans) chromatin remodeling factor is critical for establishing lineage-specific chromatin states during early mammalian development. However, the role of SMARCA4 in tissue-specific gene regulation during embryogenesis remains poorly defined. To investigate the genome-wide binding landscape of SMARCA4 in differentiating tissues, we engineered a Smarca4FLAG knock-in mouse line. Using ChIP-seq, we identified ∼51,000 SMARCA4-associated regions across six embryonic mouse tissues (forebrain, hindbrain, neural tube, heart, limb, and face) at mid-gestation (E11.5). The majority of these regions was distal from promoters and showed dynamic occupancy, with most distal SMARCA4 sites (73%) confined to a single or limited subset of tissues. To further characterize these regions, we profiled active and repressive histone marks in the same tissues and examined the intersection of informative chromatin states and SMARCA4 binding. This revealed distinct classes of distal SMARCA4-associated elements characterized by activating and repressive chromatin signatures that were associated with tissue-specific up- or down-regulation of gene expression and relevant active/repressed biological pathways. We further demonstrate the predicted active regulatory properties of SMARCA4-associated elements by retrospective analysis of tissue-specific enhancers and direct testing of SMARCA4-bound regions in transgenic mouse assays. Our results indicate a dual active/repressive function of SMARCA4 at distal regulatory sequences in vivo and support its role in tissue-specific gene regulation during embryonic development.