RESUMO
The histone H3 lysine 4-specific methyltransferase SETD1A is associated with transcription activation and is considered a key epigenetic regulator that modulates the cell cycle and metastasis in triple-negative breast cancer cells. However, the clinical role of SETD1A in estrogen receptor (ER)-positive breast cancer cells remains unclear. Here, we examined whether SETD1A is a potential target for ERα-positive breast cancer therapy. SETD1A expression was upregulated in breast tumor tissue compared to that in normal breast tissue. Moreover, ER-target genes regulated by SETD1A were particularly enriched in cell cycle and cancer pathways. SETD1A is involved in histone H3K4 methylation, subsequent recruitment of ERα, and the establishment of accessible chromatin structure at the enhancer region of ERα target genes. In addition to ERα target genes, other cell survival genes were also downregulated by SETD1A depletion in MCF-7 cells, leading to significant decrease in cell proliferation and migration, and spontaneous induction of apoptosis. We also found that miR-1915-3p functioned as a novel regulator of SETD1A expression in breast cells. Importantly, the growth of tamoxifen-resistant MCF-7 cells was effectively repressed by SETD1A knockdown. These results indicate that SETD1A may serve as a molecular target and prognostic indicator in ERα-positive breast cancer.
Assuntos
Neoplasias da Mama/genética , Movimento Celular/genética , Receptor alfa de Estrogênio/genética , Regulação Neoplásica da Expressão Gênica/genética , Histona-Lisina N-Metiltransferase/genética , Apoptose/efeitos dos fármacos , Apoptose/genética , Neoplasias da Mama/tratamento farmacológico , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Células MCF-7 , MicroRNAs/genética , Tamoxifeno/farmacologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genéticaRESUMO
The actin-like protein of the SWI/SNF complex, BAF53A, regulates gene expression by the gene-specific chromatin remodeling of target genes. However, the function of BAF53A in the androgen receptor pathway in prostate cancer cells remains unclear. Here, we demonstrated that BAF53A positively regulates the expression of endogenous AR target genes (e.g. PSA, TMPRSS2, FKBP5, and KLK2) in LNCaP cells. It functions as a coactivator in AR-mediated transcription by interacting with other nuclear receptor coactivators, such as p300 and FLII, and is associated with AR in the presence of dihydrotestosterone (DHT). The DHT-induced recruitment of BAF53A to the proximal and distal androgen response elements (AREs) of the PSA gene in the presence of BRG1 (but not BRM) was inhibited by an AR antagonist, suggesting the coactivator function of BAF53A in the SWI/SNF complex. Depletion of BAF53A in LNCaP cells resulted in a significant decrease in growth rate. Furthermore, the expression of BAF53A in prostate cancer tissue was significantly elevated, compared to that in normal prostate tissue, and correlated with the expression of AR, and BRG1, but not BRM. Therefore, our results suggested that BAF53A plays an important role in the expression of AR target genes in prostate cancer, and can be used clinically for the treatment of prostate cancer.
Assuntos
Actinas/fisiologia , Proteínas Cromossômicas não Histona/fisiologia , Proteínas de Ligação a DNA/fisiologia , Regulação Neoplásica da Expressão Gênica , Neoplasias da Próstata/genética , Receptores Androgênicos/metabolismo , Actinas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Proteínas Cromossômicas não Histona/metabolismo , Proteínas de Ligação a DNA/metabolismo , Humanos , Masculino , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Ativação TranscricionalRESUMO
The development and immune evasion of cancer stem cells (CSCs) limit the efficacy of currently available anticancer therapies. Recent studies have shown that epigenetic reprogramming regulates the expression of characteristic marker proteins and tumor plasticity associated with cancer cell survival and metastasis in CSCs. CSCs also possess unique mechanisms to evade external attacks by immune cells. Hence, the development of new strategies to restore dysregulated histone modifications to overcome cancer resistance to chemotherapy and immunotherapy has recently attracted attention. Restoring abnormal histone modifications can be an effective anticancer strategy to increase the therapeutic effect of conventional chemotherapeutic and immunotherapeutic drugs by weakening CSCs or by rendering them in a naïve state with increased sensitivity to immune responses. In this review, we summarize recent findings regarding the role of histone modifiers in the development of drug-resistant cancer cells from the perspectives of CSCs and immune evasion. In addition, we discuss attempts to combine currently available histone modification inhibitors with conventional chemotherapy or immunotherapy.
Assuntos
Código das Histonas , Neoplasias , Humanos , Histonas/metabolismo , Evasão da Resposta Imune , Neoplasias/tratamento farmacológico , Neoplasias/genética , Células-Tronco Neoplásicas/metabolismoRESUMO
Rationale: Approximately 30-40% of estrogen receptor (ER)-positive breast cancer (BC) cases recur after tamoxifen therapy. Thus, additional studies on the mechanisms underlying tamoxifen resistance and more specific prognostic biomarkers are required. In this study, we investigated the role of the SET domain containing 1A (SETD1A), a histone H3-lysine 4 (H3K4) methyltransferase, in the development of tamoxifen resistance in BC. Methods: The relationship between tamoxifen resistance and SETD1A protein level was investigated using resistant cell lines derived from the parent BC cells. Biochemical and molecular assays, such as RNA-sequencing, reverse transcription-quantitative polymerase chain reaction, chromatin-immunoprecipitation, and protein-binding assays, were used to identify the SETD1A target gene in tamoxifen-resistant BC cells. Additionally, the role of SETD1A in cancer stem cells (CSCs) was investigated using CSCs isolated from tamoxifen-resistant BC cells. Comprehensive transcriptome analysis and immunofluorescence staining using clinical datasets and tissue microarray were performed to determine the correlation between the expression of the SETD1A-SRY-box transcription factor 2 (SOX2) pair and recurrence in tamoxifen-treated patients with BC. Results: SETD1A was expressed at higher levels in tamoxifen-resistant BC cells than in primary BC cells. Notably, SETD1A-depleted tamoxifen-resistant MCF-7 cells showed restored sensitivity to tamoxifen, whereas SETD1A overexpression in MCF-7 cells resulted in decreased sensitivity. SETD1A is recruited to the SOX2 gene via its interaction with SOX2, thereby enhancing the expression of SOX2 genes in tamoxifen-resistant BC cells. The growth of tamoxifen-resistant cells and CSCs was effectively suppressed by SETD1A knockdown. In addition, high levels of SETD1A and SOX2 were significantly correlated with a low survival rate in patients with ER-positive tamoxifen-resistant BC. Conclusion: Our findings provide the first evidence of the critical role of the SETD1A-SOX2 axis in tamoxifen-resistant BC cells, implying that SETD1A may serve as a molecular target and prognostic indicator of a therapeutic response in patients with tamoxifen-resistant BC.
Assuntos
Neoplasias da Mama , Tamoxifeno , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Resistencia a Medicamentos Antineoplásicos , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Feminino , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Células MCF-7 , Fatores de Transcrição SOXB1/genética , Tamoxifeno/farmacologia , Tamoxifeno/uso terapêuticoRESUMO
Mixed lineage leukemia proteins (MLL) are the key histone lysine methyltransferases that regulate expression of diverse genes. Aberrant activation of MLL promotes leukemia as well as solid tumors in humans, highlighting the urgent need for the development of an MLL inhibitor. We screened and isolated MLL1-binding ssRNAs using SELEX (Systemic Evolution of Ligands by Exponential enrichment) technology. When sequences in sub-libraries were obtained using next-generation sequencing (NGS), the most enriched aptamers-APT1 and APT2-represented about 30% and 26% of sub-library populations, respectively. Motif analysis of the top 50 sequences provided a highly conserved sequence: 5Î-A[A/C][C/G][G/U][U/A]ACAGAGGG[U/A]GG[A/C] GAGUGGGU-3Î. APT1, APT2, and APT5 embracing this motif generated secondary structures with similar topological characteristics. We found that APT1 and APT2 have a good binding activity and the analysis using mutated aptamer variants showed that the site information in the central region was critical for binding. In vitro enzyme activity assay showed that APT1 and APT2 had MLL1 inhibitory activity. Three-dimensional structure prediction of APT1-MLL1 complex indicates multiple weak interactions formed between MLL1 SET domain and APT1. Our study confirmed that NGS-assisted SELEX is an efficient tool for aptamer screening and that aptamers could be useful in diagnosis and treatment of MLL1-mediated diseases.
RESUMO
PURPOSE-: To assess the pathological differentiation grade in the patients with extrahepatic bile duct adenocarcinoma (EBDA) using diffusion-weighted imaging (DWI) at 3.0-T MR. METHODS-: Sixty-eight patients who were clinically and histologically diagnosed with EBDA underwent abdominal DWI within 2 weeks before surgery. The lesion signal intensity, signal intensity ratio of the lesion and hepar (SIR-LH) value, and apparent diffusion coefficient (ADC) value in patients with EBDA were retrospectively analysed. RESULTS: -In the 68 patients, 22 well-differentiated, 36 moderately-differentiated, and 10 poorly-differentiated EBDAs were histopathological confirmed. These EBDAs exhibited hyper-intensity on DWI in 95.59% of patients. Hyper-intensity lesions were found in 90.91% of patients with good-differentiation, in 97.22% with moderate-differentiation and in 100% with poor-differentiation. There showed no statistical difference for the lesion signal intensity (P=0.426) and SIR-LH value (P=0.766) on DWI among three groups. The median ADC value of the well-differentiated, moderately-differentiated and poorly-differentiated EBDAs were 1.506×10-3mm2/s, 1.275×10-3mm2/s and 1.154×10-3mm2/s, respectively. As the pathological differentiation grade decreased, the lesion ADC value of EBDA gradually declined (x2=51.220, P=0.000). The ADC value <1.184×10-3mm2/s can predict the poorly-differentiated EBDA with a sensitivity of 100% and a specificity of 94.83%. The ADC value >1.316×10-3mm2/s can forecast the well-differentiated EBDA with a sensitivity of 100% and a specificity of 84.78%. CONCLUSIONS-: The histopathological differentiation grade of EBDA can be detected non-invasively using DWI at 3.0-T MR.