Departments of Malignant Hematology and Experimental Therapeutics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33613.
Department of Immunology and Malignant Hematology, Tianjin Cancer Hospital, Tianjin, China.
Cancer Cell. 2012 Oct 16;22(4):506-523. doi: 10.1016/j.ccr.2012.09.003.
We investigated the transcriptional and epigenetic repression of miR-29 by MYC, HDAC3, and EZH2 in mantle cell lymphoma and other MYC-associated lymphomas. We demonstrate that miR-29 is repressed by MYC through a corepressor complex with HDAC3 and EZH2. MYC contributes to EZH2 upregulation via repression of the EZH2 targeting miR-26a, and EZH2 induces MYC via inhibition of the MYC targeting miR-494 to create positive feedback. Combined inhibition of HDAC3 and EZH2 cooperatively disrupted the MYC-EZH2-miR-29 axis, resulting in restoration of miR-29 expression, downregulation of miR-29-targeted genes, and lymphoma growth suppression in vitro and in vivo. These findings define a MYC-mediated miRNA repression mechanism, shed light on MYC lymphomagenesis mechanisms, and reveal promising therapeutic targets for aggressive B-cell malignancies.
我们研究了 MYC、HDAC3 和 EZH2 对套细胞淋巴瘤和其他与 MYC 相关的淋巴瘤中 miR-29 的转录和表观遗传抑制作用。我们证明 miR-29 被 MYC 通过与 HDAC3 和 EZH2 形成的核心抑制复合物抑制。MYC 通过抑制 EZH2 的靶向 miR-26a 而上调 EZH2，EZH2 通过抑制 MYC 的靶向 miR-494 诱导 MYC，从而产生正反馈。联合抑制 HDAC3 和 EZH2 协同破坏了 MYC-EZH2-miR-29 轴，导致 miR-29 的表达恢复，miR-29 靶向基因下调，体外和体内淋巴瘤生长受到抑制。这些发现定义了一种 MYC 介导的 miRNA 抑制机制，阐明了 MYC 淋巴瘤发生机制，并揭示了侵袭性 B 细胞恶性肿瘤有希望的治疗靶点。
