Department of Pathology.
Eugene McDermott Center for Human Growth and Development.
J Clin Invest. 2018 May 1;128(5):1937-1955. doi: 10.1172/JCI95089. Epub 2018 Apr 9.
Altered epigenetic reprogramming contributes to breast cancer progression and metastasis. How the epigenetic reader mediates breast cancer progression remains poorly understood. Here, we showed that the epigenetic reader zinc finger MYND-type containing 8 (ZMYND8) is induced by HIF-1 and HIF-2 in breast cancer cells and also upregulated in human breast tumors, and is correlated with poor survival of patients with breast cancer. Genetic deletion of ZMYND8 decreases breast cancer cell colony formation, migration, and invasion in vitro, and inhibits breast tumor growth and metastasis to the lungs in mice. The ZMYND8's oncogenic effect in breast cancer requires HIF-1 and HIF-2. We further showed that ZMYND8 interacts with HIF-1α and HIF-2α and enhances elongation of the global HIF-induced oncogenic genes by increasing recruitment of BRD4 and subsequent release of paused RNA polymerase II in breast cancer cells. ZMYND8 acetylation at lysines 1007 and 1034 by p300 is required for HIF activation and breast cancer progression and metastasis. These findings uncover a primary epigenetic mechanism of HIF activation and HIF-mediated breast cancer progression, and discover a possible molecular target for the diagnosis and treatment of breast cancer.
表观遗传重编程导致乳腺癌的进展和转移。然而，表观遗传阅读器如何介导乳腺癌的进展仍知之甚少。在这里，我们发现表观遗传阅读器含锌指 MYND 结构域蛋白 8（ZMYND8）在乳腺癌细胞中被 HIF-1 和 HIF-2 诱导，并且在人类乳腺癌肿瘤中也上调，并且与乳腺癌患者的不良生存相关。ZMYND8 的基因缺失可降低乳腺癌细胞的集落形成、迁移和侵袭能力，抑制小鼠乳腺癌肿瘤的生长和向肺部的转移。ZMYND8 在乳腺癌中的致癌作用需要 HIF-1 和 HIF-2。我们进一步表明，ZMYND8 与 HIF-1α 和 HIF-2α 相互作用，并通过增加 BRD4 的募集和随后暂停的 RNA 聚合酶 II 的释放，增强了全局 HIF 诱导的致癌基因的延伸，从而在乳腺癌细胞中增强了 HIF 的激活和乳腺癌的进展和转移。由 p300 介导的 ZMYND8 赖氨酸 1007 和 1034 的乙酰化对于 HIF 的激活和乳腺癌的进展和转移是必需的。这些发现揭示了 HIF 激活和 HIF 介导的乳腺癌进展的主要表观遗传机制，并发现了诊断和治疗乳腺癌的可能分子靶标。
