RESUMEN
Methyltransferase-like protein 3 (METTL3) plays critical roles in acute myeloid leukemia (AML) progression, however, the mechanism of abnormal overexpression of METTL3 in AML remain elusive. In the current study, we uncovered that Yin Yang 1 (YY1) binds to the promoter region of METTL3 as a transcription factor and promotes its expression, which in turn enhances the proliferation of AML cells. Mechanistically, YY1 binds to HDAC1/3 and regulates METTL3 expression in a moderate liquid-liquid phase separation (LLPS) manner. After mutation of the HDAC-binding site of YY1 or HDAC inhibitor (HDACi) treatment, YY1 was separated from HDAC1/3, which resulted in an excessive LLPS state, thereby inhibiting the expression of METTL3 and the proliferation of AML cells. In conclusion, our study clarified the regulatory mechanism of the abnormal expression of METTL3 in AML, revealed the precise "Yin-Yang" regulatory mechanism of YY1 from the perspective of LLPS degree, and provided new ideas for the precise diagnosis and treatment of AML.
Asunto(s)
Histona Desacetilasa 1 , Leucemia Mieloide Aguda , Metiltransferasas , Factor de Transcripción YY1 , Humanos , Sitios de Unión , Proliferación Celular/genética , Histona Desacetilasa 1/metabolismo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Metiltransferasas/genética , Metiltransferasas/metabolismo , Regiones Promotoras Genéticas/genética , Factor de Transcripción YY1/genética , Factor de Transcripción YY1/metabolismoRESUMEN
Lung cancer is the most prevalent and observed type of cancer in Xuanwei County, Yunnan, South China. Lung cancer in this area is called Xuanwei lung cancer. However, its pathogenesis remains largely unknown. To date, a number of studies have shown that microRNA (miR)218 functions as a tumor suppressor in multiple types of cancer. However, the role of miR218 and its regulatory gene network in Xuanwei lung cancer have yet to be investigated. The current study identified that the expression levels of miR218 in XWLC05 cells were markedly lower compared with those in immortalized lung epithelial BEAS2B cells. The present study also demonstrated that overexpression of miR218 could decrease cell proliferation, invasion, viability and migration in Xuanwei lung cancer cell line XWLC05 and NSCLC cell line NCIH157. Additionally, the results revealed that overexpression of miR218 could induce XWLC05 and NCIH157 cell apoptosis by arresting the cell cycle at G2/M phase. Finally, the present study demonstrated that overexpression of miR218 could lead to a significant increase in phosphatase and tensin homolog (PTEN) and YY1 transcription factor (YY1), and a decrease in Bcell lymphoma 2 (BCL2) and BMI1 protooncogene, polycomb ring finger (BMI1) at the mRNA and protein level in XWLC05 and NCIH157 cell lines. However, we did not observe any remarkable difference in the roles of miR218 and miR218mediated regulation of BCL2, BMI1, PTEN and YY1 expression in the progression of Xuanwei lung cancer. In conclusion, miR218 could simultaneously suppress cell proliferation and tumor invasiveness and induce cell apoptosis by increasing PTEN and YY1 expression, while decreasing BCL2 and BMI1 in Xuanwei lung cancer. The results demonstrated that miR218 might serve a vital role in tumorigenesis and progression of Xuanwei lung cancer and overexpression of miR218 may be a novel approach for the treatment of Xuanwei lung cancer.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/genética , Regulación hacia Abajo , Neoplasias Pulmonares/genética , MicroARNs/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Ciclo Celular , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Supervivencia Celular , China , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares/metabolismo , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Complejo Represivo Polycomb 1/genética , Complejo Represivo Polycomb 1/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Factor de Transcripción YY1/genética , Factor de Transcripción YY1/metabolismoRESUMEN
To study the effects of berberine on the gene mRNA expressions of BMP4 transcriptional pathways and brown/white adipose tissue conversion transcriptional pathways in visceral white adipose tissues(VWAT) in type 2 diabetic hamsters and explore the relevant mechanisms. The obese insulin-resistant hamster model were induced by using high-fat diet, and then the type 2 diabetic hamster model was created through injection with low-dose streptozotocin in the obese insulin-resistant hamster model. After the modeling, the hamsters were randomly divided into normal control, obese insulin-resistant, type 2 diabetic and berberine-treated diabetic groups. After the nine-week treatment, real-time quantitative PCR was used to measure the changes in gene mRNA expressions of VWAT BMP4 transcriptional pathways, brown/white adipose tissue conversion transcriptional pathways and their target genes in different groups. The results showed that the gene mRNA expressions of BMP4, BMPRâ ¡, BMPRlA, Smad1, Smad5, Smad8, p38/MAPK, ATF2, PRDM16, C/EBPß, PGC1α, PPARγ and brown adipose tissue-specific genes was decreased and that of Smad6, Smurf1 and white adipose tissue-specific genes was increased in VWAT of model hamsters. Treatment with berberine regulated BMP4 transcriptional pathways and brown adipose tissue transcriptional pathways and induced the gene mRNA expression of brown adipose tissue-specific genes in VWAT to develop browning gene phenotype of white adipose tissues, and then improved fat-induced insulin resistance. These findings indicated that BMP4 transcriptional pathways involved in the formation of fat-induced visceral white adipose tissues insulin resistance (FIVWATIR) and the browning molecular mechanism of white adipose tissues induced by berberine.