USP22 drives colorectal cancer invasion and metastasis via epithelial-mesenchymal transition by activating AP4.

Yongmin Li,Bingyang Li,Yanmei Yang,Yanlong Liu,Fuxun Chen,Jingwen Li,Binbin Cui,He Liu

doi:10.18632/oncotarget.15950

Abstract

Ubiquitin specific peptidase 22 (USP22), a putative cancer stem cell marker, is overexpressed in liver metastases of colorectal cancer (CRC). However, the mechanism by which USP22 promotes CRC metastasis remains largely unknown. Here, we report that USP22 and AP4 are simultaneously overexpressed during TGF-β1-induced CRC cell epithelial-mesenchymal transition (EMT). USP22 up-regulation enhances CRC cell migration and invasion and EMT-related marker and AP4 expression, but these effects are partly blocked by AP4 knockdown. In addition, USP22 binds to the promoter region of AP4 to activate its transcription. In vivo, elevated USP22 expression promotes CRC cell metastasis to the lungs in nude mice, as evidenced by the fact that CRC metastatic nodules stain deeply positive for USP22 and AP4. In human CRC tissues, the genes encoding USP22 and AP4 are overexpressed in metastatic liver lesions compared with primary cancer tissues, and their overexpression is significantly associated with poor CRC patient survival. These findings indicate that USP22 and AP4 may serve as prognostic markers for predicting the risk of developing distant metastases in CRC.

Highlights

High levels of Ubiquitin specific peptidase 22 (USP22) and AP4 are significantly correlated with liver metastasis and poor prognoses in colorectal cancer (CRC) patients. These findings indicate that USP22 promotes CRC invasion and metastasis by inducing epithelial-mesenchymal transition (EMT) via AP4 activation
Consistent with the above observations, USP22 depletion decreased N-cadherin and vimentin expression levels and increased E-cadherin expression levels (Figure 3G–3H). These results indicate that USP22 increases CRC cell migration and invasion abilities by promoting EMT
Similar changes in cell migration and invasion were observed in the scratch and transwell assays (Figure 4C–4F). These results indicate that both USP22 and AP4 participate in EMT and that AP4 may be a downstream molecule of USP22

Summary

Introduction

In many types of cancer cells, including bladder, liver, ovarian, breast and CRC cells [12], EMT reduces adhesion with basal cells to enhance invasion and migration ability, promoting tumor metastasis to distant organs [13,14,15]. Some transcription factors, such as TGF-β1, SNAIL, SLUG, ZEB1, ZEB2 and TWIST, Colorectal cancer (CRC), one of the most common malignant tumors, is the second most common cause of cancer mortality worldwide due in part to its high tendency to recur and metastasize [1]. There are no effective treatments that can selectively control CRC metastasis, and elucidating the molecular mechanisms underlying CRC metastasis and identifying effective disease prevention and treatment modalities remain important goals in CRC research

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Conclusion