SMURF1-mediated ubiquitination of ARHGAP26 promotes ovarian cancer cell invasion and migration

摘要

Rho GTPase-activating protein 26 (ARHGAP26) is a negative regulator of the Rho family that converts the small GTP-binding protein RhoA (GTP-RhoA) to its inactive GDP-bound form and is a putative tumor suppressor gene associated with cell growth and migration. Here, the involvement of ARHGAP26 in ovarian cancer cell proliferation and migration was investigated. In this study, low ARHGAP26 expression was observed in ovarian cancer tissues and was associated with a poor overall survival and higher β-catenin expression in patients with ovarian cancer. A2780 and HEY cells with ARHGAP26 upregulation showed decreased cell proliferation, migration, and invasion, along with decreased GTP-RhoA, β-catenin, VEGF, MMP2, and MMP7 expression. ARHGAP26 upregulation in A2780 cells also inhibited lung metastasis in vivo. SKOV3 cells with ARHGAP26 downregulation demonstrated an inverse effect, which was inhibited by ARHGAP26 overexpression or DKK1, an antagonist of the β-catenin pathway. SMURF1, an E3 ubiquitin ligase, interacted with and induced ubiquitination of ARHGAP26. ARHGAP26 upregulation in SKOV3 cells significantly inhibited SMURF1 upregulation-induced cell migration and invasion. Overall, SMURF1-mediated ubiquitination of ARHGAP26 may promote invasion and migration of ovarian cancer cells via the β-catenin pathway. Ovarian cancer: Suppressing the spread A member of a protein family known to suppress tumors could help tackle ovarian cancer metastasis. Ovarian cancer remains challenging to treat because the molecular mechanisms inherent in the disease are poorly understood. Hongping Li at Shenzhen Children’s Hospital, Yuanfang Zhu at Bao’an Maternity and Child Health Hospital, and co-workers showed that low levels of a tumor-suppressing protein, Rho GTPase-activating protein 26 (ARHGAP26), promote the invasion and migration of ovarian cancer cells. The team took tumor and healthy tissue samples from 85 patients and confirmed that reduced levels of ARHGAP26 in the cancerous tissues coincided with an increase in an enzyme involved in protein degradation. This enzyme-led destruction of ARHGAP26 may enable cancer metastasis. The team backed up their hypothesis by observing reduced cancer cell proliferation in mice with high levels of ARHGAP26.