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.
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.
Electronic supplementary material
The online version of this article (10.1186/s12977-019-0467-0) contains supplementary material, which is available to authorized users.
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