Binding of USP4 to cortactin enhances cell migration in HCT116 human colon cancer cells

• Published in: The FASEB journal 2023-05, Vol.37 (5), p.e22900-n/a
• Main Authors: Yun, Sun‐Il, Kwak, Chulhwan, Lee, Song‐Yi, Shin, Sanghee, Oh, Changsuk, Kim, Jong‐Seo, Rhee, Hyun‐Woo, Kim, Kyeong Kyu
• Format: Article
• Language: English
• Subjects: beta Catenin - metabolism; cell migration; Cell Movement - physiology; colon cancer; Colonic Neoplasms; Cortactin; Cortactin - metabolism; deubiquitinating enzyme; HCT116 Cells; Humans; Ubiquitin-Specific Proteases - metabolism; USP4
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.202201337RRR

Ubiquitin‐specific protease 4 (USP4) is highly overexpressed in colon cancer and acts as a potent protooncogenic protein by deubiquitinating β‐catenin. However, its prominent roles in tumor formation and migration in cancer cells are not fully understood by its deubiquitinating enzyme (DUB) activity on β‐catenin. Thus, we investigated an additional role of USP4 in cancer. In this study, we identified cortactin (CTTN), an actin‐binding protein involved in the regulation of cytoskeleton dynamics and a potential prognostic marker for cancers, as a new cellular interacting partner of USP4 from proximal labeling of HCT116 cells. Additionally, the role of USP4 in CTTN activation and promotion of cell dynamics and migration was investigated in HCT116 cells. We confirmed that interacting of USP4 with CTTN increased cell movement. This finding was supported by the fact that USP4 overexpression in HCT116 cells with reduced expression of CTTN was insufficient to promote cell migration. Additionally, we observed that USP4 overexpression led to a significant increase in CTTN phosphorylation, which is a requisite mechanism for cell migration, by regulating Src/focal adhesion kinase (FAK) binding to CTTN and its activation. Our results suggest that USP4 plays a dual role in cancer progression, including stabilization of β‐catenin as a DUB and interaction with CTTN to promote cell dynamics by inducing CTTN phosphorylation. Therefore, this study demonstrates that USP4 is important for cancer progression and is a good target for treating or preventing cancer. A summary scheme of this study. CTTN interacts and forms a complex with the Src‐FAK complex. However, USP4 overexpression can induce an increase in CTTN phosphorylation and dissociation of the p‐CTTN from Src‐FAK‐CTTN‐USP4 complex, which promotes cell dynamics.