LSD1 destabilizes FBXW7 and abrogates FBXW7 functions independent of its demethylase activity

Abstract

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. degradation | DNA damage repair | SCF E3 ligase | ubiquitylation L SD1 (also known as KDM1A) was the first histone demethylase identified as a transcriptional repressor to regulate gene expression via catalyzing the demethylation of mono-and dimethylated histone 3 lysine 4 (H3K4Me1, H3K4Me2) (1). Subsequent studies demonstrated that LSD1 also demethylates H3K9 (Me1 and Me2) to trigger gene activation programs (2). In addition to histone 3, recent studies showed that LSD1 also acts as demethylase of nonhistone proteins, such as p53 (3), E2F1 (4), and HIF-1α (5). Furthermore, LSD1 was shown to cooperate with multiple transcriptional regulators, such as CoREST (2), NuRD (6), and SIRT1/ HDAC (7). Through these activities, LSD1 serves as a master regulator of gene expression and protein function and is actively involved in many biological processes.LSD1 is overexpressed in many human cancers which is associated with poor patient survival (8). Increased preclinical data validated LSD1 as an attractive cancer target, resulting in extensive drug discovery efforts (9). So far, most of LSD1 studies focused on its demethylase activity and associated biological functions. Likewise, all drug discovery efforts on LSD1 targeting were directed to find the demethylase inhibitors (9). However, whether LSD1 has other activities/functions independent of its demethylase activity, and what is the underlying mechanism remain largely unknown, although a recent study showed that ZNF217 naturally interacts with LSD1 to coordinately regulate gene expression independently of its demethylase functions in a prostate cancer model (10).The tumor suppressor FBXW7 functions as a well-characterized substrate recognition subunit of SCF (SKP1-CUL1-F-box protein) E3 ubiquitin ligase (11,12). SCF FBXW7 promotes ubiquitylation and degradation of a large number of oncogenic substrates such as Cyclin E, c-JUN,...

LSD1 contributes to programmed oocyte death by regulating the transcription of autophagy adaptor SQSTM1/p62

“…However, there are some differences in the mechanism. According to Chao's and Lan's studies, LSD1 destabilizes target protein independent of its demethylase activity (Chao et al, ; Lan et al, ). In our study, LSD1 regulates the transcription of p62 depending on its demethylase activity.…”

Targeting the GFI1/1B—CoREST Complex in Acute Myeloid Leukemia

“…This is relevant because in the majority of AML cases, TP53 is not mutated and it can be re-activated (95). KDM1A also binds as pseudosubstrate to the tumor suppressor and ubiquitin ligase FBXW7 (96). This results in FBXW7 auto-ubiquitination and subsequent proteasomal and lysosomal degradation.…”

Myeloid FBW7 deficiency disrupts redox homeostasis and aggravates dietary-induced insulin resistance

“…As depicted in Fig. 3 E, we found that PKM2 was polyubiquitinated by wild-type FBW7α, but not the enzymatically dead mutant (ΔF-box-FBW7) [ 34 ] ( Fig. 4 E).…”