The Molecular and Biological Function of MEF2D in Leukemia.

Myocyte enhancer factor 2 (MEF2) is a key transcription factor (TF) in skeletal, cardiac, and neural tissue development and includes four isoforms: MEF2A, MEF2B, MEF2C, and MEF2D. These isoforms significantly affect embryonic development, nervous system regulation, muscle cell differentiation, B- and T-cell development, thymocyte selection, and effects on tumorigenesis and leukemia. This chapter describes the multifaceted roles of MEF2 family proteins, covering embryonic development, nervous system regulation, and muscle cell differentiation. It further elucidates the contribution of MEF2 to various blood and immune cell functions. Specifically, in B-cell precursor acute lymphoblastic leukemia (BCP-ALL), MEF2D is aberrantly expressed and forms a fusion protein with BCL9, CSF1R, DAZAP1, HNRNPUL1, and SS18. These fusion proteins are closely related to the pathogenesis of leukemia. In addition, it specifically introduces the regulatory effect of MEF2D fusion protein on the proliferation and growth of B-cell acute lymphoblastic leukemia (B-ALL) cells. Finally, we detail the positive feedback loop between MEF2D and IRF8 that significantly promotes the progression of acute myeloid leukemia (AML) and the importance of the ZMYND8-BRD4 interaction in regulating the IRF8 and MYC transcriptional programs. The MEF2D-CEBPE axis is highlighted as a key transcriptional mechanism controlling the block of leukemic cell self-renewal and differentiation in AML. This chapter starts with the structure and function of MEF2 family proteins, specifically summarizing and analyzing the role of MEF2D in B-ALL and AML, mediating the complex molecular mechanisms of transcriptional regulation and exploring their implications for human health and disease.

Identification of a novel MEF2C::SS18L1 fusion in childhood acute B-lymphoblastic leukemia.

PURPOSE: Leukemia-associated fusion genes are closely related to the occurrence, development, diagnosis, and treatment of leukemia. DNA microarrays and second-generation sequencing have discovered multiple B-ALL fusion genes. We identified a novel MEF2C::SS18L1 fusion gene in a child diagnosed with B-ALL. This study investigates the oncogenicity and prognosis of this fusion gene in B-ALL. METHODS: A child with B-ALL who has a MEF2C::SS18L1 fusion is reported as a newly discovered case. Compared the breakpoints, structural domains, clinical phenotypes, and differential expression genes of MEF2C::SS18L1 and MEF2D::SS18.Using "ONCOFUSE" software, the carcinogenicity of MEF2C::SS18L1 is predicted. Using whole transcriptome sequencing, we analyze the breakpoints and the secondary structure of the fusion protein. Further, we compared the structures, differentially expressed genes, and clinical phenotypes of MEF2D and MEF2C fusion genes by DESeq, GO functional enrichment, and flow cytometry immunophenotyping analysis. RESULTS: Whole transcriptome sequencing identified a MEF2C::SS18L1 fusion transcript in a 3-year-old child with B-ALL. The MADS box, MEF structural domain, HJURP_C structural domain, and TAD I structural domain of MEF2C, and the QPGY structural domain of SS18L1, make up the fusion protein. "Oncofuse" found a 0.99 Bayesian probability that the fusion gene drives cancer. The breakpoint positions, fusion protein secondary structures, differentially expressed genes, and clinical characteristics of this patient were identical to those with MEF2D::SS18 fusion gene. CONCLUSION: We identified a novel MEF2C::SS18L1 fusion gene in childhood ALL, which shares similar structural and clinical characteristics with MEF2D::SS18. Further studies with more samples should be conducted in future.

CircVCAN promotes glioma progression through the miR-488-3p/MEF2C-JAGGED1 axis.

Gliomas are the most prevalent primary malignant brain tumors worldwide. Growing evidences indicate that circular RNAs (circRNAs) play an important role in the regulation of biological behavior of tumors. We aimed to investigate the role and mechanism of circVCAN in glioma. RNase R treatment was utilized to assess the cyclic properties of circVCAN. CircVCAN, miR-488-3p, and myocyte enhancer factor 2C (MEF2C) levels in glioma tissues and cells were detected by reverse transcription real-time polymerase chain reaction (RT-qPCR), and the localization of them in glioma cells was determined with fluorescence in situ hybridization. Furthermore, a variety of biologically functional assessments were used to validate the role of circVCAN in glioma. The regulatory mechanisms of circVCAN, miR-488-3p, and MEF2C were further confirmed by double luciferase reporter gene assay, RNA immunoprecipitation and RNA pull-down assay, and the binding of MEF2C to JAGGED1 was revealed by chromatin immunoprecipitation. Additionally, a xenograft tumor model was constructed to demonstrate the effect of circVCAN on tumor growth in vivo. Our results indicated that circVCAN was more stable than its linear RNA and was significantly upregulated in gliomas. CircVCAN overexpression stimulated glioma cells to proliferate and metastasize, but circVCAN silencing exerted the opposite effect. Meanwhile, silencing circVCAN inhibited tumor growth in vivo. Moreover, we found that circVCAN interacted with miR-488-3p to regulate MEF2C expression, and miR-488-3p inhibition or MEF2C overexpression reversed the inhibitory effect on malignant bio-behaviors mediated by circVCAN knockdown in glioma cells. MEF2C promoted the transcription of JAGGED1, and circVCAN knockdown reduced the binding between MEF2C and JAGGED1. Collectively, circVCAN is a carcinogenic circRNA in glioma, and the circVCAN/miR-488-3p/MEF2C-JAGGED1 axis could serve as a potential target for the management of glioma.

Class I and II Histone Deacetylase Inhibitors as Therapeutic Modulators of Dilated Cardiac Tissue-Derived Mesenchymal Stem/Stromal Cells.

The prevalence of dilated cardiomyopathy (DCM) is increasing globally, highlighting the need for innovative therapeutic approaches to prevent its onset. In this study, we examined the energetic and epigenetic distinctions between dilated and non-dilated human myocardium-derived mesenchymal stem/stromal cells (hmMSCs) and assessed the effects of class I and II HDAC inhibitors (HDACi) on these cells and their cardiomyogenic differentiation. Cells were isolated from myocardium biopsies using explant outgrowth methods. Mitochondrial and histone deacetylase activities, ATP levels, cardiac transcription factors, and structural proteins were assessed using flow cytometry, PCR, chemiluminescence, Western blotting, and immunohistochemistry. The data suggest that the tested HDAC inhibitors improved acetylation and enhanced the energetic status of both types of cells, with significant effects observed in dilated myocardium-derived hmMSCs. Additionally, the HDAC inhibitors activated the cardiac transcription factors Nkx2-5, HOPX, GATA4, and Mef2C, and upregulated structural proteins such as cardiac troponin T and alpha cardiac actin at both the protein and gene levels. In conclusion, our findings suggest that HDACi may serve as potential modulators of the energetic status and cardiomyogenic differentiation of human heart hmMSCs. This avenue of exploration could broaden the search for novel therapeutic interventions for dilated cardiomyopathy, ultimately leading to improvements in heart function.

MEF2D Functions as a Tumor Suppressor in Breast Cancer.

The myocyte enhancer factor 2 (MEF2) gene family play fundamental roles in the genetic programs that control cell differentiation, morphogenesis, proliferation, and survival in a wide range of cell types. More recently, these genes have also been implicated as drivers of carcinogenesis, by acting as oncogenes or tumor suppressors depending on the biological context. Nonetheless, the molecular programs they regulate and their roles in tumor development and progression remain incompletely understood. The present study evaluated whether the MEF2D transcription factor functions as a tumor suppressor in breast cancer. The knockout of the MEF2D gene in mouse mammary epithelial cells resulted in phenotypic changes characteristic of neoplastic transformation. These changes included enhanced cell proliferation, a loss of contact inhibition, and anchorage-independent growth in soft agar, as well as the capacity for tumor development in mice. Mechanistically, the knockout of MEF2D induced the epithelial-to-mesenchymal transition (EMT) and activated several oncogenic signaling pathways, including AKT, ERK, and Hippo-YAP. Correspondingly, a reduced expression of MEF2D was observed in human triple-negative breast cancer cell lines, and a low MEF2D expression in tissue samples was found to be correlated with a worse overall survival and relapse-free survival in breast cancer patients. MEF2D may, thus, be a putative tumor suppressor, acting through selective gene regulatory programs that have clinical and therapeutic significance.

Aberrant ecotropic viral integration site-1 (EVI-1) and myocyte enhancer factor 2 C gene (MEF2C) in adult acute myeloid leukemia are associated with adverse t (9:22) & 11q23 rearrangements.

Acute myeloid leukemia (AML) shows multiple chromosomal translocations & point mutations which can be used to refine risk-adapted therapy in AML patients. Ecotropic viral integration site-1 (EVI-1) & myocyte enhancer factor 2 C gene (MEF2C) are key regulatory transcription factors in hematopoiesis and leukemogenesis & both drive immune escape. This prospective study involved 80 adult de novo AML patients recruited from Oncology Center, Mansoura University, between March 2019 and July 2021. The MEF2C and EVI1 expression were measured using a Taqman probe-based qPCR assay. The results revealed that EVI1 and MEF2C expression were significantly elevated in AML patients as compared to control subjects (p = 0.001. 0.007 respectively). Aberrant expressions of EVI1 and MEF2C showed a significant negative correlation with hemoglobin levels (p = 0.034, 0.025 respectively), & bone marrow blasts (p = 0.007, 0.002 respectively). 11q23 translocation was significantly associated with EVI1 and MEF2C (p = 0.004 and 0.02 respectively). Also, t (9;22) was significantly associated with EVI1 and MEF2C (p = 0.01 and 0.03 respectively), higher expression of EVI1 and MEF2C were significantly associated with inferior outcome after induction therapy (p = 0.001 and 0.018 respectively) and shorter overall survival (p = 0.001, 0.014 respectively). In conclusion, EVI1 & MEF2C were significantly expressed in AML cases. EVI1 & MEF2C overexpression were significantly associated with 11q23 rearrangements and t (9;22) and were indicators for poor outcome in adult AML patients; These results could be a step towards personalized therapy in those patients.

Circulating miRNA-4701-3p as a predictive biomarker of cardiovascular disease which induces angiogenesis by inhibition of TOB2.

Angiogenesis is mainly regulated by the delivery of VEGF-dependent signaling to cells. However, the angiogenesis mechanism regulated by VEGF-induced miRNA is still not understood. After VEGF treatment in HUVECs, we screened the changed miRNAs through small-RNA sequencing and found VEGF-induced miR-4701-3p. Furthermore, the GFP reporter gene was used to reveal that TOB2 expression was regulated by miR-4701-3p, and it was found that TOB2 and miR-4701-3p modulation could cause angiogenesis in an in-vitro angiogenic assay. Through the luciferase assay, it was confirmed that the activation of the angiogenic transcription factor MEF2 was regulated by the suppression and overexpression of TOB2 and miR-4701-3p. As a result, MEF2 downstream gene mRNAs that induce angiogenic function were regulated. We used the NCBI GEO datasets to reveal that the expression of TOB2 and MEF2 was significantly changed in cardiovascular disease. Finally, it was confirmed that the expression of circulating miR-4701-3p in the blood of myocardial infarction patients was remarkably increased. In patients with myocardial infarction, circulating miR-4701-3p was increased regardless of age, BMI, and sex, and showed high AUC levels in specificity and sensitivity analysis (AUROC) (AUC = 0.8451, 95 % CI 0.78-0.90). Our data showed TOB2-mediated modulation of MEF2 and its angiogenesis by VEGF-induced miR-4701-3p in vascular endothelial cells. In addition, through bioinformatics analysis using GEO data, changes in TOB2 and MEF2 were revealed in cardiovascular disease. We suggest that circulating miR-4701-3p has high potential as a biomarker for myocardial infarction.

MEF2D facilitates liver metastasis of gastric cancer cells through directly inducing H1X under IL-13 stimulation.

Liver metastasis is the most common metastatic occurrence in gastric cancer patients, although the precise mechanism behind it remains unclear. Through a combination of proteomics and quantitative RT-PCR, our study has revealed a significant correlation between the upregulation of myocyte enhancer factor-2D (MEF2D) and both distant metastasis and poor prognosis in gastric cancer patients. In mouse models, we observed that overexpressing or knocking down MEF2D in gastric cancer cells respectively promoted or inhibited liver metastasis. Furthermore, our research has demonstrated that MEF2D regulates the transcriptional activation of H1X by binding to the H1X promoter. This regulation leads to the upregulation of H1X, which, in turn, promotes the in vivo metastasis of gastric cancer cells along with the upregulation of the downstream gene ß-CATENIN. Additionally, we found that the expression of MEF2D and H1X at both mRNA and protein levels can be induced by the inflammatory factor IL-13, and this induction exhibits a time gradient dependence. In human gastric cancer tissues, the expression of IL13RA1, the receptor for IL-13, positively correlates with the expression of MEF2D and H1X. IL13RA1 has been identified as an intermediate receptor through which IL-13 regulates MEF2D. In conclusion, our findings suggest that MEF2D plays a crucial role in promoting liver metastasis of gastric cancer by upregulating H1X and downstream target ß-CATENIN in response to IL-13 stimulation. Targeting MEF2D could therefore be a promising therapeutic strategy for the clinical management of gastric cancer. STATEMENT OF SIGNIFICANCE: MEF2D promotes its transcriptional activation in gastric cancer cells by binding to the H1X promoter and is upregulated by IL-13-IL13RA1, thereby promoting distant metastasis of gastric cancer.

Folding of Class IIa HDAC Derived Peptides into α-helices Upon Binding to Myocyte Enhancer Factor-2 in Complex with DNA.

Interaction of transcription factor myocyte enhancer factor-2 (MEF2) family members with class IIa histone deacetylases (HDACs) has been implicated in a wide variety of diseases. Though considerable knowledge on this topic has been accumulated over the years, a high resolution and detailed analysis of the binding mode of multiple class IIa HDAC derived peptides with MEF2D is still lacking. To fulfil this gap, we report here the crystal structure of MEF2D in complex with double strand DNA and four different class IIa HDAC derived peptides, namely HDAC4, HDAC5, HDAC7 and HDAC9. All class IIa HDAC derived peptides form extended amphipathic α-helix structures that fit snugly in the hydrophobic groove of MEF2D domain. Binding mode of class IIa HDAC derived peptides to MEF2D is very similar and occur primarily through nonpolar interactions mediated by highly conserved branched hydrophobic amino acids. Further studies revealed that class IIa HDAC derived peptides are unstructured in solution and appear to adopt a folded α-helix structure only upon binding to MEF2D. Comparison of our peptide-protein complexes with previously characterized structures of MEF2 bound to different co-activators and co-repressors, highlighted both differences and similarities, and revealed the adaptability of MEF2 in protein-protein interactions. The elucidation of the three-dimensional structure of MEF2D in complex with multiple class IIa HDAC derived peptides provide not only a better understanding of the molecular basis of their interactions but also have implications for the development of novel antagonist.

Myxoid epithelioid smooth muscle tumor of the vulva: A distinct entity with MEF2D::NCOA2 gene fusion.

Smooth muscle tumors are the most common mesenchymal tumors of the female genital tract, including the vulva. Since vulvar smooth muscle tumors are rare, our understanding of them compared to their uterine counterparts continues to evolve. Herein, we present two cases of morphologically distinct myxoid epithelioid smooth muscle tumors of the vulva with novel MEF2D::NCOA2 gene fusion. The tumors involved 24 and 37-year-old women. Both tumors presented as palpable vulvar masses that were circumscribed, measuring 2.8 and 5.1 cm in greatest dimension. Histologically, they were composed of epithelioid to spindle-shaped cells with minimal cytologic atypia and prominent myxoid matrix. Rare mitotic figures were present (1-3 mitotic figures per 10 high-power field (HPF)), and no areas of tumor necrosis were identified. By immunohistochemistry, the neoplastic cells strongly expressed smooth muscle actin, calponin, and desmin, confirming smooth muscle origin. Next-generation sequencing identified identical MEF2D::NCOA2 gene fusions. These two cases demonstrate that at least a subset of myxoid epithelioid smooth muscle tumors of the vulva represent a distinct entity characterized by a novel MEF2D::NCOA2 gene fusion. Importantly, recognition of the distinct morphologic and genetic features of these tumors is key to understanding the biological potential of these rare tumors.

CircRNA Larp4b/miR-298-5p/Mef2c Regulates Cardiac Hypertrophy Induced by Angiotensin II.

Cardiac hypertrophy (CH) is an early marker in the clinical course of heart failure. Circular RNAs (circRNAs) play important roles in human disease. However, the role of circ_Larp4b in myocardial hypertrophy has not been studied. Angiotensin II (Ang II) treated HL-1 cells to induce a CH cell model. Quantitative real-time polymerase chain reaction was used to detect the expression of circ_Larp4b, microRNA-298-5p, and myocyte enhancer factor 2 (Mef2c). Western blot detected the protein level of alpha-actinin-2 (ACTN2), beta-myosin heavy chain (ß-MHC), atrial natriuretic peptide (ANP), and Mef2c. The relationship between miR-298-5p and circ_Larp4b or Mef2c was verified by dual-luciferase reporter assay and RNA pull-down assay. Circ_Larp4b and Mef2c were upregulated in HL-1 cells treated with Ang II. Moreover, circ_Larp4b down-regulation regulated the progress of CH induced by Ang II. MiR-298-5p was a target of circ_Larp4b, and Mef2c was a target of miR-298-5p. Overexpressed Mef2c reversed the cell size inhibited by miR-298-5p in Ang II-induced HL-1 cells. Circ_Larp4b regulated CH progress by regulating miR-298-5p/Mef2c axis.

Whole-brain in vivo base editing reverses behavioral changes in Mef2c-mutant mice.

Whole-brain genome editing to correct single-base mutations and reduce or reverse behavioral changes in animal models of autism spectrum disorder (ASD) has not yet been achieved. We developed an apolipoprotein B messenger RNA-editing enzyme, catalytic polypeptide-embedded cytosine base editor (AeCBE) system for converting C·G to T·A base pairs. We demonstrate its effectiveness by targeting AeCBE to an ASD-associated mutation of the MEF2C gene (c.104T>C, p.L35P) in vivo in mice. We first constructed Mef2cL35P heterozygous mice. Male heterozygous mice exhibited hyperactivity, repetitive behavior and social abnormalities. We then programmed AeCBE to edit the mutated C·G base pairs of Mef2c in the mouse brain through the intravenous injection of blood-brain barrier-crossing adeno-associated virus. This treatment successfully restored Mef2c protein levels in several brain regions and reversed the behavioral abnormalities in Mef2c-mutant mice. Our work presents an in vivo base-editing paradigm that could potentially correct single-base genetic mutations in the brain.

LncRNA CASC2 Alleviates Renal Interstitial Inflammation and Fibrosis through MEF2C Downregulation-Induced Hinderance of M1 Macrophage Polarization.

INTRODUCTION: Long noncoding RNA (lncRNA) cancer susceptibility candidate 2 (CASC2) alleviates the progression of diabetic nephropathy by inhibiting inflammation and fibrosis. This study investigated how CASC2 impacts renal interstitial fibrosis (RIF) through regulating M1 macrophage (M1) polarization. METHOD: Nine-week-old mice underwent unilateral ureteral obstruction (UUO) establishment. Macrophages were induced toward M1 polarization using lipopolysaccharide (LPS) in vitro and cocultured with fibroblasts to examine how M1 polarization influences RIF. LnCeCell predicted that CASC2 interacted with myocyte enhancer factor 2 C (MEF2C), which was validated by dual-luciferase reporter assay. CASC2/MEF2C overexpression was achieved by lentivirus-expressing lncRNA CASC2 injection in vivo or CASC2 and MEF2C transfection in vitro. Renal injury was evaluated through biochemical analysis and hematoxylin-eosin/Masson staining. Macrophage infiltration and M1 polarization in the kidney and/or macrophages were detected by immunofluorescence, flow cytometry, and/or quantitative reverse transcription polymerase chain reaction (qRT-PCR). Expressions of CASC2, MEF2C, and markers related to inflammation/M1/fibrosis in the kidney/macrophages/fibroblasts were analyzed by qRT-PCR, fluorescence in situ hybridization, enzyme-linked immunosorbent assay, and/or Western blot. RESULT: In the kidneys of mice, CASC2 was downregulated and macrophage infiltration was promoted time-dependently from days 3 to 14 post-UUO induction; CASC2 overexpression alleviated renal histological abnormalities, hindered macrophage infiltration and M1 polarization, downregulated renal function markers serum creatinine and blood urea nitrogen and inflammation/M1/fibrosis-related makers, and offset UUO-induced MEF2C upregulation. LncRNA CASC2 overexpression inhibited fibroblast fibrosis and M1 polarization in cocultured fibroblasts with LPS-activated macrophages. Also, CASC2 bound to MEF2C and inhibited its expression in LPS-activated macrophages. Furthermore, MEF2C reversed the inhibitory effects of lncRNA CASC2 overexpression. CONCLUSION: CASC2 alleviates RIF by inhibiting M1 polarization through directly downregulating MEF2C expression. CASC2 might represent a promising value of future investigations on treatment for RIF.

Brusatol enhances MEF2A expression to inhibit RCC progression through the Wnt signalling pathway in renal cell carcinoma.

Renal cell carcinoma (RCC) is the most aggressive subtype of kidney tumour with a poor prognosis and an increasing incidence rate worldwide. Brusatol, an essential active ingredient derived from Brucea javanica, exhibits potent antitumour properties. Our study aims to explore a novel treatment strategy for RCC patients. We predicted 37 molecular targets of brusatol based on the structure of brusatol, and MEF2A (Myocyte Enhancer Factor 2A) was selected as our object through bioinformatic analyses. We employed various experimental techniques, including RT-PCR, western blot, CCK8, colony formation, immunofluorescence, wound healing, flow cytometry, Transwell assays and xenograft mouse models, to investigate the impact of MEF2A on RCC. MEF2A expression was found to be reduced in patients with RCC, indicating a close correlation with MEF2A deubiquitylation. Additionally, the protective effects of brusatol on MEF2A were observed. The overexpression of MEF2A inhibits RCC cell proliferation, invasion and migration. In xenograft mice, MEF2A overexpression in RCC cells led to reduced tumour size compared to the control group. The underlying mechanism involves the inhibition of RCC cell proliferation, invasion, migration and epithelial-mesenchymal transition (EMT) through the modulation of Wnt/ß-catenin signalling. Altogether, we found that MEF2A overexpression inhibits RCC progression by Wnt/ß-catenin signalling, providing novel insight into diagnosis, treatment and prognosis for RCC patients.

A Ubiquitin-Dependent Switch on MEF2D Senses Pro-Metastatic Niche Signals to Facilitate Intrahepatic Metastasis of Liver Cancer.

Effective treatment for metastasis, a leading cause of cancer-associated death, is still lacking. To seed on a distal organ, disseminated cancer cells (DCCs) must adapt to the local tissue microenvironment. However, it remains elusive how DCCs respond the pro-metastatic niche signals. Here, systemic motif-enrichment identified myocyte enhancer factor 2D (MEF2D) as a critical sensor of niche signals to regulate DCCs adhesion and colonization, leading to intrahepatic metastasis and recurrence of liver cancer. In this context, MEF2D transactivates Itgb1 (coding ß1-integrin) and Itgb4 (coding ß4-integrin) to execute temporally unique functions, where ITGB1 recognizes extracellular matrix for early seeding, and ITGB4 acts as a novel sensor of neutrophil extracellular traps-DNA (NETs-DNA) for subsequent chemotaxis and colonization. In turn, an integrin-FAK circuit promotes a phosphorylation-dependent USP14-orchastrated deubiquitination switch to stabilize MEF2D via circumventing degradation by the E3-ubiquitin-ligase MDM2. Clinically, the USP14(pS432)-MEF2D-ITGB1/4 feedback loop is often hyper-active and indicative of inferior outcomes in human malignancies, while its blockade abrogated intrahepatic metastasis of DCCs. Together, DCCs exploit a deubiquitination-dependent switch on MEF2D to integrate niche signals in the liver mesenchyme, thereby amplifying the pro-metastatic integrin-FAK signaling. Disruption of this feedback loop is clinically applicable with fast-track potential to block microenvironmental cues driving metastasis.

MEF2C and miR-194-5p: New Players in Triple Negative Breast Cancer Tumorigenesis.

Among breast cancer (BC) subtypes, the most aggressive is triple negative BC (TNBC), which is prone to metastasis. We previously found that microRNA (miR)-194-5p is downregulated at the early stages of TNBC brain metastasis development. Additionally, the transcription factor myocyte enhancer factor 2 (MEF2)C, a bioinformatically predicted miR-194-5p target, was increasingly expressed throughout TNBC brain metastasis formation and disease severity. However, the contributions of these two players to malignant cells' features remain undetermined. This study aimed at disclosing the role of miR-194-5p and MEF2C in TNBC tumorigenesis. The transfection of 4T1 cells with a silencer for MEF2C or with a pre-miRNA for miR-194-5p was employed to study TNBC cells' phenotypic alterations regarding epithelial and mesenchymal markers, as well as migratory capability alterations. MEF2C-silenced cells presented a decline in both vimentin and cytokeratin expression, whereas the overexpression of miR-194-5p promoted an increase in cytokeratin and a reduction in vimentin, reflecting the acquisition of an epithelial phenotype. Both treatments reduced TNBC cells' migration. These results suggest that MEF2C may determine TNBC cells' invasive properties by partially determining the occurrence of epithelial-mesenchymal transition, while the overexpression of miR-194-5p promotes a decline in TNBC cells' aggressive behavior and reinforces this miRNA's role as a tumor suppressor in TNBC.

[Clinical characteristics and outcomes of childhood B-ALL with ZNF384 and MEF2D rearrangements].

B-cell precursor acute lymphoblastic leukemia (BCP-ALL) has many subtypes with diverse clinical and biological features and outcomes. Next generation sequencing has revealed several novel subtypes, including the ZNF384 and MEF2D rearrangements. The clinical characteristics and outcomes of the largest series of BCP-ALL cases with ZNF384 and MEF2D rearrangements in an international collaborative study are described here. Patients with ZNF384 rearrangements appear to express various leukemic phenotypes, including BCP-ALL (with or without abnormal expression of myeloid markers) and B/myeloid mixed phenotype acute leukemia. We provide strong evidence that among BCP-ALL patients with a ZNF384 fusion, the partner gene is associated with demographic features and influences the outcome; particularly the EP300-ZNF384 fusion is associated with a low risk of relapse. MEF2D rearrangements have been primarily described in children and young adults with BCP-ALL. Previous research has suggested that patients with MEF2D-BCL9 fusion have a high risk of relapse. Despite having the MEF2D-HNRNPUL1 fusion gene, the prognosis was favorable. Improved diagnostic genomic testing will enable future prospective studies to clarify the clinical significance of the ZNF384 and MEF2D rearrangements in childhood and young adult BCP-ALL.

[Expression of MEF2D in Lung Adenocarcinoma and Its Correlation with Prognosis].

BACKGROUND: Myocyte enhancer factor 2D (MEF2D) can participate in the process of tumor lesions by regulating the transcription of oncogenes. In a previous study, MEF2D was demonstrated to enhance the proliferation and metastasis of lung adenocarcinoma cells A549 and H1299 by promoting the transcription of NUSAP1. The research aimed to explore the expression level and clinical significance of MEF2D in lung adenocarcinoma. METHODS: A total of 199 patients with lung adenocarcinoma were collected. Immunohistochemical staining was used to detect MEF2D expression levels in cancer and adjacent tissues. After the clinical and follow-up data were collated, the correlation between MEF2D expression level and clinical characteristics and prognosis of the patients was analyzed. RESULTS: In the lung adenocarcinoma, the high expression rate of MEF2D in cancer tissues was significantly higher than that in adjacent tissues (P<0.05). According to immunohistochemical score, MEF2D expression level in lung adenocarcinoma tissues was correlated with tumor differentiation, N stage, M stage and intrapulmonary metastasis (P<0.05). Kaplan-Meier analysis showed that patients with low MEF2D expression had significantly better prognosis than patients with high MEF2D expression (P<0.05). Cox multivariate analysis showed that MEF2D expression level, M stage, N stage and bone metastasis of lung cancer were independent risk factors for prognosis of lung adenocarcinoma patients. CONCLUSIONS: MEF2D expression level is closely related to the metastasis of lung adenocarcinoma and other clinical characteristics, and can be used as an independent risk factor for the prognosis of patients with lung adenocarcinoma, which has the potential to be developed as a clinical diagnosis and treatment target of lung adenocarcinoma.

Mutation of TP53 Confers Ferroptosis Resistance in Lung Cancer Through the FOXM1/MEF2C Axis.

Ferroptosis is a highly regulated tumor suppressor process. Loss or mutation of TP53 can cause changes in sensitivity to ferroptosis. Mutations in TP53 may be associated with the malignant or indolent progression of ground glass nodules in early lung cancer, but whether ferroptosis may also be involved in determining this biological process has not yet been determined. Using in vivo and in vitro gain- and loss-of-function approaches, this study used clinical tissue for mutation analysis and pathological research to show that wild-type TP53 inhibited the expression of forkhead box M1 (FOXM1) by binding to peroxisome proliferator-activated receptor-γ coactivator 1α, maintaining the mitochondrial function and thus affecting the sensitivity to ferroptosis. This function was absent in mutant cells, resulting in overexpression of FOXM1 and ferroptosis resistance. Mechanistically, FOXM1 activated the transcription level of myocyte-specific enhancer factor 2C in the mitogen-activated protein kinase signaling pathway, leading to stress protection when exposed to ferroptosis inducers. This study provides new insights into the mechanism of association between TP53 mutation and ferroptosis tolerance, which can aid a deeper understanding of the role of TP53 in the malignant progression of lung cancer.

Comprehensive analysis and identification of the circ_0084615/miR-451a/MEF2D axis in benzo(a)pyrene exposed tumor cells in hepato-carcinogenesis.

Hepatocellular carcinoma (HCC) is caused by genetic and epigenetic alterations, as well as abnormal lifestyle and dietary habits, including contaminated food intake. Benzo(a)pyrene (B[a]P), derived from deep-fried meats, is regarded as the main dietary factor for tumorigenesis in epidemiological investigations. Although various studies have illustrated the adverse effects of B[a]P in malignancy through cell and animal models, the correlation between B[a]P exposure and clinical data remain to be explored. In the present study, we analyzed and identified novel B[a]P-associated circular RNA (circRNA) from microarray databases of liver tumor cells and HCC patient samples. Considering that circRNA regulates mRNA as a miRNA sponge, molecular circRNA-miRNA-mRNA interactions based on the stimulation of B[a]P exposure were predicted and established. Furthermore, up-regulated circ_0084615 in B[a]P-treated tumor cells was verified as a miRNA sponge via fluorescence in situ hybridization (FISH) assays, and the repression between circ_0084615 and target miR-451a exhibited a contrasting effect on hepatocarcinogenesis. Therefore, we performed integrated bioinformatics analysis and molecular experiments to establish the circ_0084615/miR-451a/MEF2D pathway, which provided a better understanding of the adverse effects of fried food preference on human health.