RESUMEN
Enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of polycomb repressive complex 2 (PRC2). Dysregulation of EZH2 causes alteration of gene expression and functions, thereby promoting cancer development. The regulatory function of EZH2 varies across different tumor types. The canonical role of EZH2 is gene silencing through catalyzing the trimethylation of lysine 27 of histone H3 (H3K27me3) in a PRC2-dependent manner. Accumulating evidence indicates that EZH2 has an H3K27me3-independent function as a transcriptional coactivator and plays a critical role in cancer initiation, development, and progression. In this review, we summarize the regulation and function of EZH2 and focus on the current understanding of the noncanonical role of EZH2 in cancer.
Asunto(s)
Proteína Potenciadora del Homólogo Zeste 2/genética , Neoplasias/genética , Animales , Expresión Génica/genética , Silenciador del Gen/fisiología , Histonas/genética , Humanos , Complejo Represivo Polycomb 2/genéticaRESUMEN
BACKGROUND: Adult T-cell leukemia (ATL) is an aggressive neoplasm caused by human T-cell leukemia virus type 1 (HTLV-1). ATL carries a poor prognosis due to chemotherapy resistance. Thus, it is urgent to develop new treatment strategies. Hypericin (HY) is a new-type of photosensitizer in the context of photodynamic therapy (PDT) due to its excellent photosensitizing properties and anti-tumor activities. RESULTS: In the present study, we investigated the efficacy of hypericin in ATL cells. Clinically achievable concentrations of hypericin in association with PDT induced the inhibition of cell proliferation in ATL cell lines with minimal effect on peripheral blood CD4+ T lymphocytes. Moreover, hypericin-PDT treatment caused apoptosis and G2/M phase cell cycle arrest in leukemic cells. Western blot analyses revealed that hypericin-PDT treatment resulted in downregulation of Bcl-2 and enhanced the expression of Bad, cytochrome C, and AIF. Cleavage of caspases-3/-7/-9/-8, Bid, and PARP was increased in hypericin-PDT-treated ATL cells. In a luciferase assay, hypericin-PDT treatment was able to activate the promoter activity of Bax and p53, resulting in enhanced expression of Bax and p53 proteins. Finally, hypericin-PDT treatment suppressed the expression of viral protein HBZ and Tax by blocking the promoter activity via HTLV-1 5'LTR and 3'LTR. CONCLUSIONS: Our results revealed that hypericin-PDT is highly effective against ATL cells by induction of apoptosis and suppression of viral transcription. These studies highlight the promising use of hypericin-PDT as a targeted therapy for ATL.
Asunto(s)
Apoptosis/efectos de los fármacos , Virus Linfotrópico T Tipo 1 Humano/efectos de los fármacos , Leucemia-Linfoma de Células T del Adulto/tratamiento farmacológico , Luz , Perileno/análogos & derivados , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/farmacología , Antracenos , Apoptosis/efectos de la radiación , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/efectos de la radiación , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/efectos de la radiación , Virus Linfotrópico T Tipo 1 Humano/efectos de la radiación , Humanos , Modelos Biológicos , Perileno/farmacología , Transcripción Genética/efectos de los fármacos , Transcripción Genética/efectos de la radiación , Ensayo de Tumor de Célula MadreRESUMEN
Long noncoding RNAs (lncRNAs) are RNA molecules longer than 200 nucleotides that regulate gene expression at the transcriptional and post-transcriptional levels. Emerging evidence showed that lncRNAs play important roles in a wide range of biological processes, including cell proliferation, apoptosis, and tumorigenesis. The infection of virus generally can regulate the expression of the cellular lncRNA expression. The lncRNAs which encoded by virus can also modulate the expression of the hosts' gene which is critical for virus infection. Here, we summarized the recent progress on long noncoding RNA and its relationship with virus, especially the function of long noncoding RNA on virus-induced oncogenesis. Studies on lncRNAs and their relationship with viruses may give new insights into virus-host interactions and therapy of related diseases.
Asunto(s)
ARN Largo no Codificante/genética , Virosis/metabolismo , Animales , Apoptosis , Carcinogénesis , Línea Celular Tumoral , Proliferación Celular , Epigénesis Genética , Perfilación de la Expresión Génica , Regulación Viral de la Expresión Génica , Redes Reguladoras de Genes , Genoma Humano , Humanos , Ratones , Neoplasias/genética , Neoplasias/metabolismo , Virosis/genética , Virus/genética , Virus/metabolismoRESUMEN
We studied the effect of celastrol on the proliferation and apoptosis of adult T-cell leukemia (ATL) cells. After treating adult T-cell leukemia cell lines with different concentrations of celastrol, we analyzed the cell proliferation by MTT and colony formation assays. Flow cytometry was conducted to detect cell apoptosis by Annexin V-FITC/PI staining. Western blotting and dual-luciferase reporter assay were done to study the mechanism how celastrol suppressed the growth of adult T-cell leukemia cells. Celastrol could significantly inhibit the proliferation of adult T-cell leukemia cells, and induce apoptosis of ATL cells. With the increase of the concentration of celastrol, the ratio of Bax/Bcl-2 protein was up-regulated. The Caspase-3/7 protein was cleaved and activated after treatment with celastrol. Moreover, the expression of HTLV-1-encoded viral protein Tax was significantly inhibited in the celastrol treated cells. Taken together, these results indicated that celastrol effectively inhibited the proliferation of adult T-cell leukemia cells by regulating the expression of Bcl-2 family protein, and induced cell apoptosis by activating Caspase dependent pathway. In addition, celastrol could inhibit the expression of viral protein Tax. This study will provide an experimental basis for the clinical application of celastrol in the treatment of adult T-cell leukemia.