Department of Dermatology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, 75390-9133, USA; Cancer Biology Graduate Program, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, 75390-9133, USA.
Department of Dermatology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, 75390-9133, USA.
Cell Rep. 2014 Jan 16;6(1):81-92. doi: 10.1016/j.celrep.2013.12.001. Epub 2013 Dec 27.
Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive sarcomas that develop sporadically or in neurofibromatosis type 1 (NF1) patients. There is no effective treatment for MPNSTs and they are typically fatal. To gain insights into MPNST pathogenesis, we utilized an MPNST mouse model that allowed us to study the evolution of these tumors at the transcriptome level. Strikingly, in MPNSTs we found upregulation of a chromatin regulator, Brd4, and show that BRD4 inhibition profoundly suppresses both growth and tumorigenesis. Our findings reveal roles for BET bromodomains in MPNST development and report a mechanism by which bromodomain inhibition induces apoptosis through induction of proapoptotic Bim, which may represent a paradigm shift in therapy for MPNST patients. Moreover, these findings indicate epigenetic mechanisms underlying the balance of anti- and proapoptotic molecules and that bromodomain inhibition can shift this balance in favor of cancer cell apoptosis.
恶性外周神经鞘瘤（MPNST）是一种高度侵袭性肉瘤，可散发性发生或出现在神经纤维瘤病 1 型（NF1）患者中。目前尚无针对 MPNST 的有效治疗方法，此类肿瘤通常是致命的。为了深入了解 MPNST 的发病机制，我们利用 MPNST 小鼠模型，能够在转录组水平上研究这些肿瘤的演变。引人注目的是，我们在 MPNST 中发现了染色质调节剂 Brd4 的上调，并表明 BRD4 抑制可显著抑制生长和肿瘤发生。我们的研究结果揭示了 BET 溴结构域在 MPNST 发展中的作用，并报告了溴结构域抑制通过诱导促凋亡 Bim 诱导细胞凋亡的机制，这可能代表了 MPNST 患者治疗的范式转变。此外，这些发现表明了调控抗凋亡和促凋亡分子平衡的表观遗传机制，并且溴结构域抑制可以使这种平衡有利于癌细胞凋亡。
