RESUMO
Both EZH2 and its homolog EZH1 function as histone H3 Lysine 27 (H3K27) methyltransferases and repress the transcription of target genes. Dysregulation of H3K27 trimethylation (H3K27me3) plays an important role in the development and progression of cancers such as hepatocellular carcinoma (HCC). This study investigated the relationship between the expression of EZH1/2 and the level of H3K27me3 in HCC. Additionally, the role of EZH1/2 in cell growth, tumorigenicity, and resistance to sorafenib were also analyzed. Both the lentiviral knockdown and the pharmacological inhibition of EZH1/2 (UNC1999) diminished the level of H3K27me3 and suppressed cell growth in liver cancer cells, compared with EZH1 or EZH2 single knockdown. Although a significant association was observed between EZH2 expression and H3K27me3 levels in HCC samples, overexpression of EZH1 appeared to contribute to enhanced H3K27me3 levels in some EZH2lowH3K27me3high cases. Akt suppression following sorafenib treatment resulted in an increase of the H3K27me3 levels through a decrease in EZH2 phosphorylation at serine 21. The combined use of sorafenib and UNC1999 exhibited synergistic antitumor effects in vitro and in vivo. Combination treatment canceled the sorafenib-induced enhancement in H3K27me3 levels, indicating that activation of EZH2 function is one of the mechanisms of sorafenib-resistance in HCC. In conclusion, sorafenib plus EZH1/2 inhibitors may comprise a novel therapeutic approach in HCC.
Assuntos
Antineoplásicos/uso terapêutico , Benzamidas/uso terapêutico , Carcinoma Hepatocelular/terapia , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Indazóis/uso terapêutico , Neoplasias Hepáticas/terapia , Piperazinas/uso terapêutico , Complexo Repressor Polycomb 2/antagonistas & inibidores , Piridonas/uso terapêutico , Sorafenibe/uso terapêutico , Idoso , Animais , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Feminino , Terapia Genética , Humanos , Neoplasias Hepáticas/genética , Masculino , Camundongos SCID , Pessoa de Meia-Idade , Complexo Repressor Polycomb 2/genéticaRESUMO
We report a 34-year-old woman with eating epilepsy induced not only by eating but also seeing foods made of minced meat. In her early 20s of age, she started having simple partial seizures (SPS) as flashback and epigastric discomfort induced by particular foods. When she was 33 years old, she developed SPS, followed by secondarily generalized tonic-clonic seizure (sGTCS) provoked by eating a hot dog, and 6 months later, only seeing the video of dumpling. We performed video electroencephalogram (EEG) monitoring while she was seeing the video of soup dumpling, which most likely caused sGTCS. Ictal EEG showed rhythmic theta activity in the left frontal to mid-temporal area, followed by generalized seizure pattern. In this patient, seizures were provoked not only by eating particular foods but also by seeing these. This suggests a form of epilepsy involving visual stimuli.