RESUMO
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.
Assuntos
Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Histona Desmetilases/deficiência , Mieloma Múltiplo/patologia , Proteínas Nucleares/deficiência , Animais , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Carcinogênese/patologia , Adesão Celular/efeitos dos fármacos , Adesão Celular/genética , Desdiferenciação Celular/efeitos dos fármacos , Desdiferenciação Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Células Clonais , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Histona Desmetilases/metabolismo , Histonas/metabolismo , Indazóis/farmacologia , Fatores Reguladores de Interferon/metabolismo , Lisina/metabolismo , Metilação , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Mieloma Múltiplo/genética , Mutação/genética , Proteínas Nucleares/metabolismo , Fenótipo , Piridonas/farmacologia , Transcrição Gênica/efeitos dos fármacosRESUMO
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.