MIB1 upregulates IQGAP1 and promotes pancreatic cancer progression by inducing ST7 degradation

Abstract

Despite recent progress in cancer treatment, the prognosis of patients with pancreatic cancer still remains poor. Pancreatic tumors are reported to display high molecular heterogeneity. Elucidating the molecular mechanisms underlying pancreatic cancer progression is essential for improving patient treatment and survival. The overexpression of E3 ubiquitin ligase mind bomb 1 (MIB1) was previously described in pancreatic cancer cells, where it enhanced tumor cell proliferation. However, the role of MIB1 in pancreatic cancer progression remains elusive. In the present study, we confirmed that MIB1 expression is elevated in pancreatic cancer tissues and that high levels of MIB associate with unfavorable prognosis. Overexpression of MIB1 enhanced proliferation and invasion of pancreatic cancer cells both in vitro and in vivo. We further investigated the molecular mechanisms downstream of MIB1 and observed for the first time that MIB1 targets suppressor of tumorigenicity 7 protein (ST7), previously described as suppressor of tumorigenicity, for proteasomal degradation. Furthermore, we found that ST7 suppressed tumor growth by downregulating IQ motif containing GTPase activating protein 1 (IQGAP1) in pancreatic tumor cells. Thus, these data show that MIB1 promotes pancreatic cancer progression by inducing ST7 degradation followed by downregulation of IQGAP1 in pancreatic cancer cells. In conclusion, our research shows that the MIB1/ ST7/IQGAP1 axis is essential for pancreatic cancer progression, and MIB1 inhibition may serve as a novel therapeutic strategy in patients with pancreatic cancer.

CEMIP, acting as a scaffold protein for bridging GRAF1 and MIB1, promotes colorectal cancer metastasis via activating CDC42/MAPK pathway

“…Then we identified MIB1 as a potential E3 ubiquitin ligase of GRAF1. MIB1 was reported as an E3 ubiquitin ligase that promoted the ubiquitination and degradation of Notch ligands [ 34 ], and played an important role in growth, metastasis, and micro-environment of tumor [ 35 – 37 ]. In the current research, we proved that MIB1 interacted with the RhoGAP domain of GRAF1, and negatively regulated the ubiquitination of GRAF1, which supported that GRAF1 was a ubiquitinated substrate of MIB1 in CRC.…”

Prognostic signature construction of energy metabolism-related genes in pancreatic cancer

“…The risk scores calculated using the 7 prognostic features were determined as independent prognostic factors for pancreatic cancer patients and were validated using the GSE57495 data. These 7 prognostic features are GNB3, which has been shown to affect OS in pancreatic cancer ( 22 ); GNG7, which can be used as a therapeutic target in pancreatic cancer ( 23 ); IQGAP1, the overexpression of which promotes pancreatic cancer progression ( 24 ), and 4 other genes (ACACB GNA15, STXBP1, VAMP2) that have not yet been reported in pancreatic cancer.…”

Deubiquitination of FBP1 by USP7 blocks FBP1–DNMT1 interaction and decreases the sensitivity of pancreatic cancer cells to PARP inhibitors

“…Capan‐1 cells (5 × 10 6 ) with different treatments were dispersed in 100 μL PBS and inoculated subcutaneously into the left dorsal flank of nude mice. The detail of procedure was described previously [ 18 ]. Experimental procedures were performed according to guidelines set forth by the Chinese National Institutes of Health and approved by the Ethical Committee on Animal Experiments of the Huazhong University of Science and Technology in Wuhan, China (Animal license number: 2502).…”