USP22 deubiquitinates and stabilizes ERK1/2 to promote colorectal cancer progression.

Extracellular signal-regulated kinase 1/2 (ERK1/2), a key effector involved in cell proliferation, differentiation, and apoptosis, is frequently dysregulated in colorectal cancer (CRC) tumorigenesis and confers extensive therapeutic resistance, with the mechanism to be elucidated. Deubiquitinases (DUBs) catalyze the removal of ubiquitin from substrates and result in altered protein stability, activity, relocalization, or interaction; DUBs have been shown to be closely related to tumorigenesis and are thus attractive drug targets. Ubiquitin-specific protease 22 (USP22) is involved in the occurrence, proliferation, and metastasis of CRC, but the underlying mechanism remains unclear. Here, we report that USP22 expression is correlated with ERK1/2 expression in CRCs. USP22 specifically interacted with ERK1/2 and stabilized it by removing the K48 polyubiquitin chains, thereby activating the ERK signaling pathway to promote CRC. Moreover, we identified ACT001 as a novel USP22 inhibitor, and ACT001 induced substantial ERK1/2 ubiquitination and its subsequent degradation, efficiently suppressing the growth of CRC cells in vitro and in vivo by targeting USP22. Overall, this study revealed the mechanism underlying the role of hyperregulated ERK1/2 in CRC development, providing further insights into the pathology of CRC and the potential applicability of USP22-ERK1/2 as a therapeutic target in CRC.