ZUP1 suppresses ulcerative colitis and colitis-associated colorectal cancer through K63-linked deubiquitination of ERK1/2

Ulcerative colitis (UC) is a chronic inflammatory disorder of the colorectum and a major risk factor for colitis-associated colorectal cancer (CAC). However, the role of deubiquitinases (DUBs) in the progression from UC to CAC remains incompletely understood. We identified ZUP1 as a markedly down-regulated deubiquitinase in UC and CAC by RNA sequencing, public dataset analyses, screening with multiple machine-learning algorithms, and validation in clinical specimens. Functionally, ZUP1 deficiency aggravated colitis-associated inflammation and barrier damage, and promoted the proliferation, migration, and invasion of colorectal cancer cells. Mechanistically, ZUP1 directly interacted with ERK1/2 and removed K63-linked ubiquitin chains from ERK1/2, thereby disrupting MEK1/2–ERK1/2 interaction and restraining ERK1/2 phosphorylation. In addition, ERK activation up-regulated c-JUN, which in turn bound to the ZUP1 promoter and repressed its transcription, forming a positive feedback loop. In conclusion, these findings identify ZUP1 as a previously unrecognized suppressor of UC and CAC progression and suggest that the ZUP1–ERK1/2–c-JUN axis may serve as a therapeutic target in UC and CAC.