Upregulation of itchy E3 ubiquitin protein ligase contributes to endometrial cancer through promoting forkhead box P1 degradation

Objective: Endometrial cancer (EC) is one of the most prevalent cancers affecting the female reproductive system and originates from the uterine epithelium, posing a significant health burden to postmenopausal women. As an E3 ubiquitin ligase, itchy E3 ubiquitin protein ligase (ITCH) plays a key role in the progression of multiple kinds of solid cancers, but its function in EC remains unclear. This work aims to explore the roles of ITCH during the carcinogenesis of EC. Material and Methods: The messenger RNA (mRNA) level of ITCH in 47 paired EC tissue and adjacent non-tumor controls was examined by quantitative polymerase chain reaction. The protein level of ITCH in formalin-fixed paraffin-embedded EC tissue and adjacent non-tumor controls from 47 patients with EC was detected by immunohistochemistry. Data on the RNA levels of ITCH and forkhead box P1 (FOXP1), along with prognostic information for 541 patients with EC, were obtained from the Human Protein Atlas database. A chromatin immunoprecipitation assay was employed to investigate the interaction between FOXP1 and the promoter of the KRAS proto-oncogene GTPase (KRAS). Results: Both ITCH mRNA and protein levels are upregulated in EC tissues. Patients with lower ITCH expression exhibit prolonged overall survival. In EC tissue samples, ITCH protein level negatively correlates with the FOXP1 protein level. ITCH interacts with FOXP1 in EC cells and promotes its ubiquitination and subsequent degradation. FOXP1 inhibits KRAS expression in EC cells by binding to its promoter region. ITCH overexpression suppresses the FOXP1-KRAS axis, leading to increased proliferation and reduced apoptosis of EC cells. Conclusion: ITCH functions as an oncogene in EC, promoting carcinogenesis by inducing FOXP1 degradation and upregulating KRAS expression.