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.LSD1 is known to execute epigenetic regulation by forming corepressor complex with CoREST/HDACs.However,the molecular mechanisms by which cells maintain LSD 1/CoREST complex integrity are unknown.Here,we report that LSD1 protein undergoes K63-linked polyubiquitination.OTUD7B is responsible for LSD1 deubiquitination,cellular homeostasis and LSD 1/CoREST complex integrity.OTUD7B deficiency increases K63-linked ubiquitination of LSD1,which disrupts LSD 1/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.Both OTUD7B and LSD1 proteins are over-presented 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 LSD 1/CoREST corepressor complex,LSD1 turnover,and breast cancer metastasis.