USP43 directly regulates ZEB1 protein, mediating proliferation and metastasis of colorectal cancer

Abstract

Colorectal cancer is one of the most common malignant tumors of the digestive tract. In this study, we had examined the biological role of USP43 in colorectal cancer. USP43 protein and mRNA abundance in clinical tissues and five cell lines were analyzed with quantitative real-time PCR test (qRT-PCR) and western blot. USP43 overexpression treated DLD1 cells and USP43 knockdown treated SW480 cells were used to study cell proliferation, migration, colony formation, invasion, and the expression of epithelial-mesenchymal transformation (EMT) biomarkers. Moreover, ubiquitination related ZEB1 degradation was studied with qRT-PCR and western blot. The relationships between USP43 and ZEB1 were investigated with western blot, co-immunoprecipitation, migration, and invasion. USP43 was highly expressed in colorectal cancer tissues. USP43 overexpression and knockdown treatments could affect cell proliferation, colony formation, migration, invasion, and the expression of EMT associated biomarkers. Moreover, USP43 can regulate ZEB1 degradation through ubiquitination pathway. USP43 could promote the proliferation, migration, and invasion of colorectal cancer. Meanwhile, USP43 can deubiquitinate and stabilize the ZEB1 protein, which plays an important role in the function of colorectal cancer.

Overexpression of the Ubiquitin Specific Proteases USP43, USP41, USP27x and USP6 in Osteosarcoma Cell Lines: Inhibition of Osteosarcoma Tumor Growth and Lung Metastasis Development by the USP Antagonist PR619

“…For example, USP27 through stabilization of cyclin E participates in the control of primary liver tumor growth [ 36 ], and USP41 regulates the proliferation of lung cancer cells [ 37 ]. USP43 also seems to participate in the control of colorectal cancer cell proliferation [ 38 ]. Thus, it can be hypothesized that USP6, USP27x, USP41 and USP43 via various mechanisms would be able to modulate OS cell proliferation and thus primary tumor growth.…”

“…For example, high expression of USP43 in breast and colon cancers has been shown to be associated with tumor development by increasing the ability of tumor cells to migrate. These effects are closely correlated with the ability of these proteins to stimulate EMT [ 38 , 39 ]. These data suggest that in OS in which we show increased expression of USP43, this protein may participate in the regulation of EMT, a cellular process largely involved in OS progression.…”

“…Indeed, despite OS arise from transformed cells of mesenchymal origin, numerous studies demonstrated that an overexpression of EMT-transcription factors such as Snails, ZEBs or Twist allow an EMT-like phenomena that promotes the invasive properties of OS cells [ 40 , 41 ]. Interestingly, ZEB-1 whose expression is strongly increased in OS tissues compared to normal bone tissues, and in patients with lung metastases [ 42 ] is deubiquitinated and thus stabilized by USP43 [ 38 ]. Regarding USP27, it has been recently shown that this USP is able to regulate EMT by promoting the stabilization of Snail [ 43 ].…”

Epithelial–mesenchymal transition: The history, regulatory mechanism, and cancer therapeutic opportunities

“…296 Besides, the ubiquitination of ZEB1 involves additional E3 ubiquitin ligases such as checkpoint with Forkhead and ring finger domains (CHFR), F-box only protein 45 (FBXO45), and deubiquitinases including USP51 and USP43. [297][298][299][300] As to ZEB2, the regulation of protein stability is associated with E3 ubiquitin ligases FBXW7 and TRIM14. 301,302 These observations indicate that the regulation of ZEB proteins is rather complex in tumor progression.…”

“…Thus, TRIM26 and USP39 function in an antagonistic manner to coordinate the fate of liver cancer 296 . Besides, the ubiquitination of ZEB1 involves additional E3 ubiquitin ligases such as checkpoint with Forkhead and ring finger domains (CHFR), F‐box only protein 45 (FBXO45), and deubiquitinases including USP51 and USP43 297–300 . As to ZEB2, the regulation of protein stability is associated with E3 ubiquitin ligases FBXW7 and TRIM14 301,302 .…”