OTUD7B Deubiquitinates LSD1 to Govern Its Binding Partner Specificity, Homeostasis, and Breast Cancer Metastasis

Abstract

Genomic amplification of OTUD7B is frequently found across human cancers. But its role in tumorigenesis is poorly understood. Lysine‐specific demethylase 1 (LSD1) is known to execute epigenetic regulation by forming corepressor complex with CoREST/histone deacetylases (HDACs). However, the molecular mechanisms by which cells maintain LSD1/CoREST complex integrity are unknown. Here, it is reported that LSD1 protein undergoes K63‐linked polyubiquitination. OTUD7B is responsible for LSD1 deubiquitination at K226/277 residues, resulting in dynamic control of LSD1 binding partner specificity and cellular homeostasis. OTUD7B deficiency increases K63‐linked ubiquitination of LSD1, which disrupts LSD1/CoREST complex formation and targets LSD1 for p62‐mediated proteolysis. Consequently, OTUD7B deficiency impairs genome‐wide LSD1 occupancy and enhances the methylation of H3K4/H3K9, therefore profoundly impacting global gene expression and abrogating breast cancer metastasis. Moreover, physiological fluctuation of OTUD7B modulates cell cycle‐dependent LSD1 oscillation, ensuring the G1/S transition. Both OTUD7B and LSD1 proteins are overpresented in high‐grade or metastatic human breast cancer, while dysregulation of either protein is associated with poor survival and metastasis. Thus, OTUD7B plays a unique partner‐switching role in maintaining the integrity of LSD1/CoREST corepressor complex, LSD1 turnover, and breast cancer metastasis.

Linear ubiquitination modification of NR6A1 by LUBAC inhibits RIPK3 kinase activity and attenuates apoptosis of vascular smooth muscle cells

“…For validation, we performed cotransfection with the Flag‐tagged NR6A1 and HA‐tagged K48, K11, and K0 Ub mutant plasmids into the rat primary VSMCs (K0 plasmid refers to the mutation of all seven Ks on the ubiquitin molecule into R, so that it can be assembled into a linear ubiquitin chain from the first methionine [M1]). [ 26 ] Next, IP for Flag was conducted, with the results showing that the main ubiquitination type of NR6A1 was M1 linear ubiquitination (Figure 4A). Literature has shown that the only E3 ubiquitin ligase complex involved in linear ubiquitination is LUBAC, and the LUBAC complex is predominantly composed of HOIP (RNF31), HOIL‐1 (RBCK1), and SHANRPIN.…”

A state-of-the-art review on LSD1 and its inhibitors in breast cancer: Molecular mechanisms and therapeutic significance

“…Mounting evidence supports that LSD1 is overexpressed in many subtypes of BC and promotes their proliferation (Pollock et al, 2012;Yang et al, 2018d;Xu et al, 2019;Wang et al, 2022), differentiation (Wu et al, 2013;Zhang et al, 2013;Ji et al, 2021), metastasis (Li et al, 2011;Qiu et al, 2018;Zheng et al, 2018;Hu et al, 2019;Gong et al, 2021), and drug resistance (Bennani-Baiti, 2012;Verigos et al, 2019;Zhou et al, 2021a;Liu et al, 2022), which makes LSD1 become a promising target for BC therapy. But the detailed mechanisms of the LSD1 in BC progression are unclear and more potential anti-tumor pathways or downstream genes are yet to clarify due to the heterogeneity of varieties of BC subtypes.…”

“…For example, miR-708 inhibits BC proliferation and invasion via directly binding to the 3′ UTR of LSD1 and reducing its level (Ma et al, 2016). In addition, epigenetic modifications such as phosphorylation (Peng et al, 2015;Feng et al, 2016;Zhou et al, 2016), acetylation (Luo et al, 2016), methylation (Liu et al, 2020a), and ubiquitination (Wu et al, 2013;Yi et al, 2016;Zhou et al, 2016;Gong et al, 2021) also contribute to the function of LSD1 (Figure 2). PKCα can phosphorylate LSD1 at S112, activating its demethylase activity and enhancing the occupancy on E-cadherin promoter, and finally promote EMT and metastasis in BC (Feng et al, 2016).…”

“…Apart from USP7 and USP22, USP28 also could remove ubiquitin modifications from LSD1, maintain its stability, and thus confer stemness to BC cells (Wu et al, 2013). Recently, OTUD7B was also found to mediate deubiquitination of LSD1 at K226/277 residues, which stabilized LSD1 and promoted its assembly into co-repressor complex (Gong et al, 2021).…”

“…Apart from as a subunit of many complexes mediating BC progression, the function of LSD1 was also regulated by several epigenetic enzymes in BC (Feng et al, 2016;Liu et al, 2020a;Gong et al, 2021). Feng et al (2016) highlighted the PKCαmediated phosphorylation of the S112 residue of LSD1 which was crucial for epithelial-mesenchymal transition (EMT) and…”