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

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. OTUD7B catalyzes K63‐linked deubiquitination of lysine‐specific demethylase 1 (LSD1), a process that is pivotal in regulating cellular homeostasis and the binding partner specificities of LSD1. OTUD7B regulates LSD1‐dependent transcriptome via modulating genome‐wide LSD1 distribution and H3K4me2 enrichment. Both proteins are overpresented in high‐grade or metastatic human breast cancer, highlighting a unique role of dysregulated OTUD7B signaling in driving breast cancer metastasis via LSD1.