Taf14 is a subunit of multiple fundamental complexes implicated in transcriptional regulation and DNA damage repair in yeast cells. Here, we investigate the association of Taf14 with the consensus sequence present in other subunits of these complexes and describe the mechanistic features that affect this association. We demonstrate that the precise molecular mechanisms and biological outcomes underlying the Taf14 interactions depend on the accessibility of binding interfaces, the ability to recognize other ligands, and a degree of sensitivity to temperature and chemical and osmotic stresses. Our findings aid in a better understanding of how the distribution of Taf14 among the complexes is mediated.

The SWI/SNF chromatin remodeling complex uses the energy of ATP hydrolysis to alter contacts between DNA and nucleosomes, allowing regions of the genome to become accessible for biological processes such as transcription. The SWI/SNF chromatin remodeler is also one of the most frequently altered protein complexes in cancer, with upwards of 20% of all cancers carrying mutations in a SWI/SNF subunit. Intense studies over the last decade have probed the molecular events associated with SWI/SNF dysfunction in cancer and common themes are beginning to emerge in how tumor-associated SWI/SNF mutations promote malignancy. In this review, we summarize current understanding of SWI/SNF complexes, their alterations in cancer, and what is known about the impact of these mutations on tumor-relevant transcriptional events. We discuss how enhancer dysregulation is a common theme in SWI/SNF mutant cancers and describe how resultant alterations in enhancer and super-enhancer activity conspire to block development and differentiation while promoting stemness and self-renewal. We also identify a second emerging theme in which SWI/SNF perturbations intersect with potent oncoprotein transcription factors AP-1 and MYC to drive malignant transcriptional programs.

Immune evasion is the process that tumor cells accelerate growth and metastasis by evading the recognition and attack of immune cells. SNF5 is one of the core subunits of SWI/SNF, which is involved in the development of a variety of malignancies. However, the functions of SNF5 in Non-Small Cell Lung Cancer (NSCLC) and the mechanism of SNF5 regulates immune evasion are still unclear. Based on this, we analyzed the expression of SNF5 and overall survival of lung cancer tissues through the cancer genome atlas (TCGA) database. Then we performed genetic gain and loss of function experiments with SNF5 using lentivirus infection and siRNA in NSCLC A549 and NCI-H1299 cells, respectively. We investigated the proliferation and immune evasion of these cells. We further explored the mechanism of SNF5 on NSCLC cells immune evasion. Our data showed that SNF5 was significantly increased in lung cancer tissues than that in normal lung tissues. Furthermore, SNF5 promoted NSCLC cells proliferation and the expressions of immune evasion-related genes. Meantime, overexpressed SNF5 reduced mortality of A549 cells when co-cultured with T cells. Moreover, SNF5 regulated the immune evasion by activating the signal transducer and activator of transcription (STAT3)/ phospho-STAT3 pathway in NSCLC cells. Together, our results validate SNF5 as a tumor oncogene and provide a new target for NSCLC treatment.

Increased stiffness of the extracellular matrix is an important hallmark of melanoma development and progression, but its regulatory role and related mechanisms remain unclear. We adapted polydimethylsiloxane (PDMS)-micropillar-based matrix platform and investigated the effect of matrix stiffness on the proliferation, epithelial-mesenchymal transition (EMT), and immune escape of melanoma cells. We observed a stiff matrix enhanced cell proliferation, EMT, and immune escape of A375 cells. Furthermore, the expression of SNF5 on the stiffer matrix was higher than that on the softer matrix. Next, we investigated whether SNF5 is an important transducer in response to matrix stiffness. Our results revealed that knockdown of SNF5 significantly decreased stiff matrix-induced activation of cell proliferation, EMT and immune escape. Meanwhile, the overexpression of SNF5 showed its ability to increase cell proliferation, invasion and immune escape by activating the STAT-3 pathway in vitro. Furthermore, SNF5 deficiency elevated the level of tumor-infiltrating CD8+T cells and decreased the number of PD-L1 positive cells in vivo. Together, our findings suggested that stiffer substrate enhanced melanoma development by upregulating SNF5 expression, and SNF5 is a key mediator of stiffer matrix-induced immune evasion of melanoma cancer cells.

BACKGROUND: SWI/SNF, a well-known ATP-dependent chromatin-remodeling complex, plays an essential role in several biological processes. SNF5, the core subunit of the SWI/SNF remodeling complex, inactivated in 95% of malignant rhabdoid tumors (MRT), highlighting its significance in tumorigenesis. However, the role of SNF5 in bladder cancer (BC) remains unknown. In this study, we aimed to investigate the function and potential clinical applicability of SNF5 in BC.
METHODS: Data from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) and Cancer Cell Line Encyclopedia (CCLE) databases were used to evaluate the clinical significance of SNF5 in BC. We performed Gene Set Enrichment Analysis (GSEA) and functional assays to investigate the role of SNF5 in BC. Genomics of Drug Sensitivity in Cancer (GDSC) and drug-susceptibility tests were performed to identify the potential value of SNF5 in the treatment of BC.
RESULTS: Low SNF5 expression conferred a poor prognosis and was significantly associated with the N-stage in BC. ROC curves indicated that SNF5 could distinguish BC from the normal tissues. In vitro and in vivo functional assays demonstrated that attenuated SNF5 expression could promote cell proliferation and enhance migration by STAT3 activation. We imputed that low SNF5 expression could confer greater resistance against conventional first-line drugs, including cisplatin and gemcitabine in BC. GDSC and drug-resistance assays suggested that low SNF5 expression renders T24 and 5637 cells high sensitivity to EGFR inhibitor gefitinib, and combination of EZH2 inhibitor GSK126 and cisplatin.
CONCLUSIONS: To the best of our knowledge, the present study, for the first time, showed that low SNF5 expression could promote cell proliferation and migration by activating STAT3 and confer poor prognosis in BC. Importantly, SNF5 expression may be a promising candidate for identifying BC patients who could benefit from EGFR-targeted chemotherapy or cisplatin in combination with EZH2 inhibitor treatment regimens.

Homocysteine (Hcy) is a strong and independent risk factor of atherosclerosis. It can accelerate atherosclerosis through increased production of inflammatory factors, especially interleukin-1 β (IL-1β), while the precise mechanisms remain to be well elucidated. In this study, we investigated the role of the tumor suppressor gene SNF5 related to switch/sucrose non-fermentable complex (SWI/SNF) in the occurrence and development of atherosclerosis induced by Hcy. Using Hyperhomocysteinemia (HHcy) atherosclerotic model with apolipoprotein E knockout (ApoE-/-) mice fed with high-methionine diet, we showed that Hcy aggravates inflammation in macrophages during the atherosclerotic plaque formation. Further analysis showed that SNF5 promotes IL-1β expression and secretion. In addition, due to the existence of H3K4 methylation signals in the vicinity of IL-1β, we found that Hcy significantly promotes the expression of H3K4me1, and lysine-specific histone demethylase 1A (KDM1A) acts as a transcriptional repressor to regulate the expression of H3K4me1 by demethylating H3K4me1. In summary, our results demonstrated that Hcy up-regulates the expression of SNF5 through KDM1A, resulting in an increased level of H3K4me1 modification and IL-1β in macrophages, which in turn promotes the formation of atherosclerosis. Our study will provide more evidence for further revealing the specific mechanism of Hcy-induced inflammation and the diagnosis, prevention, and treatment of atherosclerosis.

SNF5 is a key protein in regulating cell proliferation and apoptosis in various cancers. However, the physiological roles of SNF5 in Endometrial carcinoma (EC), which is one of the most frequent malignancies of the female reproduction worldwide, remains unclear. This study aims to investigate the role of SNF5 and its correlation with clinicopathologic characteristics in EC.
We performed immunohistochemistry to detect the SNF5 expression in 46 endometrial carcinomas and 20 normal endometrium (non-EC) specimens, as well as analyzed the correlations between SNF5 expression and clinicopathologic features of patients using a statistics software (GraphPad Prism V6.0). Western blotting had been used to confirm the protein level of SNF5 in endometrial tissues. In addition, we evaluated the correlations between SNF5 and p21 in EC.
The positive immunostaining rate for SNF5 in EC and non-EC specimens were 65% (30/46) and 25% (5/20) respectively, and the expression of SNF5 was dramatically increased in EC compared with the normal endometrium (P < 0.01). The overexpression of SNF5 was associated with the PR levels, but not with age, FIGO stage, grade, lymphatic metastasis, myometrial invasion or ER status. Knockdown of SNF5 inhibits the expression of p21.
Our results indicate that SNF5 plays an important role of promoting oncogenesis in EC. These findings open up the possibility for various novel and effective combination therapies targeting SNF5 in the EC.

The osteogenic capacities of bone marrow-derived stromal cells (BMSCs) diminish during replicative senescence, and these changes affect the success of therapeutic application of BMSCs. In this study, we sought to explore the molecular mechanisms underlying the osteogenic differentiation capacities that occur during replicative senescence. It is well known that Oct4 is a key transcription factor essential for maintaining differentiation capacities of the stem cells. In this study, we found that BMSCs at passage 6 (replicative senescent BMSCs) showed marked decreases in the osteogenic differentiation potential and the level of Oct4. These were accompanied by reduced levels of Snf5 and histone H3 lysine-4 trimethylation (H3K4me3) in the Oct4 promoter. In BMSCs at passage 2, knockdown of Snf5 diminished expression of Oct4 and disrupted the up-regulation of alkaline phosphatase (ALP) and runt-related transcription factor 2 (Runx2) after osteogenic differentiation induction, which was accompanied by a reduction in Snf5 and H3K4me3 binding to the Oct4 promoter. These findings indicate that the decreased level of Snf5 binding to the promoter region of the Oct4 gene down-regulated the expression of Oct4, which may be the mechanism underlying the decline in osteogenic capacities in replicative senescent BMSCs.

SNF5, is a core member of the SWI/SNF chromatin remodeling complex. It\'s deficiency leads to multiple types of aggressive cancer. Sézary syndrome, a leukemic variant of cutaneous T-cell lymphoma, is characterized by its resistance to apoptosis. Although the cause of apoptosis resistance is still poorly understood, recent evidence has revealed the importance of SATB1 in the apoptosis resistance of Sézary syndrome. In this study, we show that SNF5 is an upstream regulator of SATB1 in several conditions and that both are deficient in Sézary cells. Additionally, SNF5 not only controls the expression of SATB1, but also utilizes SATB1 to recruit itself to specific sites. Overexpression of SNF5 induces SATB1 expression and partially reverse apoptosis resistance phenotype in Sézary cells. These results suggest that both SNF5 and SATB1 may regulate apoptosis-related genes in Sézary syndrome. Thus, targeting SWI/SNF complex may represent a promising approach for Sézary syndrome therapy.

The current study aimed to characterize SNF5 expression and investigate the relationship between SNF5 and clinicopathological features in skull base chordoma. 48 patients diagnosed with skull base chordoma were enrolled in this study. Tissue microarray and immunohistochemistry were performed to evaluate the expression of SNF5 in skull base chordoma. Kaplan-Meier survival analysis was used to assess survival. Multivariable Cox regression analysis was used to identify risk factors affecting patient survival. The H-scores for cytoplasmic SNF5 ranged from 124.47 to 254.52. Low expression of SNF5 was correlated with shorter overall survival (OS) (p = 0.021). Patients with age > 55 years old had shorter progression free survival (PFS) and OS times than patients whose age ≤ 55 years old (p = 0.005 and 0.003, respectively). The gross total resection group showed longer PFS than the non-gross total resection group (p = 0.024). Females showed shorter PFS times than males (p = 0.033). Multivariable Cox regression analysis showed that age, extent of resection and sex were independent prognostic factors for PFS (p = 0.010, 0.013 and 0.042, respectively). Age was an independent prognostic factor for OS (p = 0.010). Our study indicate that low expression of SNF5 is associated with poor prognosis in skull base chordoma.