RESUMEN
Williams syndrome transcription factor (WSTF) is a transcription factor and tyrosine kinase. WSTF overexpression promotes migration and proliferation of various cancers, and Ser158 (WSTFS158) phosphorylation plays an important role in this process. However, the role of the other posttranslational modifications of WSTF is unknown. Here, we report that lysine (K) 426 on WSTF is acetylated by MOF and deacetylated by SIRT1. Mechanistically, male-specific lethal (MSL) 1v1 interaction with WSTF facilitates its interaction with MOF for WSTF acetylation, which in turn promotes WSTFS158 phosphorylation. The kinase and transcriptional regulatory activity of WSTF were enhanced by acetylation. WSTFK426ac levels positively and significantly correlated with tumor size, histological grade, and age. Moreover, we demonstrated that acetylated WSTF promotes cancer cell proliferation, migration, invasion, and tumor formation. In conclusion, we identified the enzymes regulating WSTF K426 acetylation, and demonstrated an acetylation-dependent mechanism that modulates the activities of WSTF and contributes to tumorigenesis. Our findings provide new clues to study WSTF-mediated normal development and disease.
Asunto(s)
Carcinogénesis/patología , Histona Acetiltransferasas/metabolismo , Neoplasias/patología , Factores de Transcripción/metabolismo , Acetilación , Animales , Carcinogénesis/genética , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Femenino , Regulación de la Expresión Génica , Células HEK293 , Histona Acetiltransferasas/genética , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Invasividad Neoplásica/genética , Trasplante de Neoplasias , Fosforilación , Procesamiento Proteico-Postraduccional , Interferencia de ARN , ARN Interferente Pequeño/genética , Sirtuina 1/genética , Sirtuina 1/metabolismo , Trasplante HeterólogoRESUMEN
Overexpression of Jumonji domain-containing 6 (JMJD6) has been reported to be associated with more aggressive breast cancer characteristics. However, the precise role of JMJD6 in breast cancer development remains unclear. Here, we demonstrate that JMJD6 has intrinsic tyrosine kinase activity and can utilize ATP and GTP as phosphate donors to phosphorylate Y39 of histone H2A.X (H2A.XY39ph). High JMJD6 levels promoted autophagy in triple negative breast cancer (TNBC) cells by regulating the expression of autophagy-related genes. The JMJD6-H2A.XY39ph axis promoted TNBC cell growth via the autophagy pathway. We show that combined inhibition of JMJD6 kinase activity and autophagy efficiently decreases TNBC growth. Together, these findings suggest an effective strategy for TNBC treatment.
Asunto(s)
Autofagia , Histonas/metabolismo , Histona Demetilasas con Dominio de Jumonji/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias de la Mama Triple Negativas/metabolismo , Animales , Femenino , Histonas/genética , Humanos , Histona Demetilasas con Dominio de Jumonji/genética , Ratones , Ratones Endogámicos BALB C , Proteínas de Neoplasias/genética , Fosforilación , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/patologíaRESUMEN
Histone H2B monoubiquitination is a key histone modification that has significant effects on chromatin higher-order structure and gene transcription. Multiple biological processes have been suggested to be tightly related to the dynamics of H2B monoubiquitination. However, a comprehensive understanding of biological roles of H2B monoubiquitination is still poorly understood. In the present study, we developed an efficient tool to disrupt endogenous H2B monoubiquitination levels by using an H2BK120R mutant construct expressed in human cells. Genome-wide microarray analysis of these cells revealed a potential global view of biological functions of H2B monoubiquitination. Bioinformatics analysis of our data demonstrated that while H2B monoubiquitination expectedly affected a number of previously reported biological pathways, we also uncovered the influence of this histone modification on many novel biological processes. Therefore, our work provided valuable information for understanding the role of H2B monoubiquitination and indicated potential directions for its further studies.
