Cancer Institute of the Second Affiliated Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, 310029 Hangzhou, China.
Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109.
Proc Natl Acad Sci U S A. 2019 Jun 18;116(25):12311-12320. doi: 10.1073/pnas.1902012116. Epub 2019 May 31.
FBXW7 acts as a typical tumor suppressor, with loss-of-function alterations in human cancers, by promoting ubiquitylation and degradation of many oncoproteins. Lysine-specific demethylase 1 (LSD1) is a well-characterized histone demethylase. Whether LSD1 has demethylase-independent activity remains elusive. Here we report that LSD1 directly binds to FBXW7 to destabilize FBXW7 independent of its demethylase activity. Specifically, LSD1 is a pseudosubstrate of FBXW7 and LSD1-FBXW7 binding does not trigger LSD1 ubiquitylation, but instead promotes FBXW7 self-ubiquitylation by preventing FBXW7 dimerization. The self-ubiquitylated FBXW7 is subjected to degradation by proteasome as well as lysosome in a manner dependent on autophagy protein p62/SQSTM1. Biologically, LSD1 destabilizes FBXW7 to abrogate its functions in growth suppression, nonhomologous end-joining repair, and radioprotection. Collectively, our study revealed a previously unknown activity of LSD1, which likely contributes to its oncogenic function. Targeting LSD1 protein, not only its demethylase activity, might be a unique approach for LSD1-based drug discovery for anticancer application.
FBXW7 作为一种典型的肿瘤抑制因子，其功能丧失改变存在于人类癌症中，通过促进许多癌蛋白的泛素化和降解。赖氨酸特异性去甲基酶 1（LSD1）是一种公认的组蛋白去甲基酶。LSD1 是否具有去甲基酶非依赖性活性仍不清楚。在这里，我们报告 LSD1 直接与 FBXW7 结合，以不依赖其去甲基酶活性的方式使 FBXW7 不稳定。具体而言，LSD1 是 FBXW7 的伪底物，LSD1-FBXW7 结合不会触发 LSD1 的泛素化，但会通过阻止 FBXW7 二聚化来促进 FBXW7 自身泛素化。自身泛素化的 FBXW7 通过自噬蛋白 p62/SQSTM1 以依赖于溶酶体的方式被蛋白酶体降解。从生物学角度来看，LSD1 使 FBXW7 不稳定，从而消除其在生长抑制、非同源末端连接修复和放射保护中的功能。总之，我们的研究揭示了 LSD1 的一个先前未知的活性，这可能有助于其致癌功能。靶向 LSD1 蛋白，而不仅仅是其去甲基酶活性，可能是 LSD1 为基础的抗癌药物发现的一种独特方法。
