| First Author | Lan H | Year | 2019 |
| Journal | Proc Natl Acad Sci U S A | Volume | 116 |
| Issue | 25 | Pages | 12311-12320 |
| PubMed ID | 31152129 | Mgi Jnum | J:276560 |
| Mgi Id | MGI:6315457 | Doi | 10.1073/pnas.1902012116 |
| Citation | Lan H, et al. (2019) LSD1 destabilizes FBXW7 and abrogates FBXW7 functions independent of its demethylase activity. Proc Natl Acad Sci U S A 116(25):12311-12320 |
| abstractText | 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. |
