Ovarian tumor deubiquitinase 6A regulates cell proliferation via deubiquitination of nucleolin and caspase‑7.

Most proteins maintain protein homeostasis via post‑translational modifications, including the ubiquitin‑proteasome system. Deubiquitinating enzymes (DUBs) have essential intercellular roles, such as responses to DNA damage, proteolysis and apoptosis. Therefore, it is important to understand DUB‑related diseases to identify DUBs that target abnormally regulated proteins in cells. Ovarian tumor deubiquitinase 6A (OTUD6A) was previously reported as a downregulated DUB in HCT116 cells with p53 knockdown. Therefore, it was expected that the relationship between OTUD6A and p53 would affect cell proliferation. In the present study, putative substrates of OTUD6A related to the p53 signaling pathway were identified. Application of liquid chromatography‑tandem mass spectrometry and proteomic analysis led to the identification of nucleolin (known to bind p53) as a binding protein. In addition, immunoprecipitation studies determined that caspase‑7, an apoptotic protein, is associated with p53 signaling and is regulated by OTUD6A. It was further identified that OTUD6A regulates the protein stability of nucleolin, but not caspase‑7. It was also demonstrated that OTUD6A acts as a respective DUB through the deubiquitination of K48‑linked polyubiquitin chain of nucleolin and the K63‑linked polyubiquitin chain of caspase‑7. Furthermore, overexpression of OTUD6A induced cell proliferation via enhancing cell cycle progression of MCF7 cells. Taken together, OTUD6A may be proposed as a target for anticancer therapy.