RESUMEN
Epigenetic changes are common alterations in cancer cells. Here, we have investigated the role of Polycomb group proteins in the establishment and maintenance of the aberrant silencing of tumor suppressor genes during transformation induced by the leukemia-associated PML-RARalpha fusion protein. We show that in leukemic cells knockdown of SUZ12, a key component of Polycomb repressive complex 2 (PRC2), reverts not only histone modification but also induces DNA demethylation of PML-RARalpha target genes. This results in promoter reactivation and granulocytic differentiation. Importantly, the epigenetic alterations caused by PML-RARalpha can be reverted by retinoic acid treatment of primary blasts from leukemic patients. Our results demonstrate that the direct targeting of Polycomb group proteins by an oncogene plays a key role during carcinogenesis.
Asunto(s)
Proteínas Portadoras/fisiología , Leucemia Promielocítica Aguda/metabolismo , Proteínas Nucleares/fisiología , Proteínas de Fusión Oncogénica/fisiología , Proteínas Represoras/metabolismo , Diferenciación Celular , Metilación de ADN , Epigénesis Genética , Silenciador del Gen , Granulocitos/fisiología , Histonas , Humanos , Proteínas de Neoplasias , Proteínas de Fusión Oncogénica/genética , Complejo Represivo Polycomb 2 , Proteínas del Grupo Polycomb , Factores de Transcripción , Tretinoina/farmacología , Células Tumorales CultivadasRESUMEN
Loss or inactivation of the histone H3K27 demethylase UTX occurs in several malignancies, including multiple myeloma (MM). Using an isogenic cell system, we found that loss of UTX leads to deactivation of gene expression ultimately promoting the proliferation, clonogenicity, adhesion, and tumorigenicity of MM cells. Moreover, UTX mutant cells showed increased in vitro and in vivo sensitivity to inhibition of EZH2, a histone methyltransferase that generates H3K27me3. Such sensitivity was related to a decrease in the levels of IRF4 and c-MYC and an activation of repressors of IRF4 characteristic of germinal center B cells such as BCL6 and IRF1. Rebalance of H3K27me3 levels at specific genes through EZH2 inhibitors may be a therapeutic strategy in MM cases harboring UTX mutations.