Abstract
Tumor metastasis is the most common cause of cancer-related deaths, yet it remains poorly understood. The transcription factor zinc-finger E-box binding homeobox 1 (ZEB1) is involved in the epithelial-to-mesenchymal transition (EMT) and plays a pivotal role in tumor metastasis. However, the underlying mechanisms of the posttranslational modification of ZEB1 remain largely unknown. Herein, we demonstrated that specific inhibition of CDK4/6 was able to block tumor metastasis of breast cancer by destabilizing the ZEB1 protein in vitro and in vivo. Mechanistically, we determined that the deubiquitinase USP51 is a bona fide target of CDK4/6. The phosphorylation and activation of USP51 by CDK4/6 is necessary to deubiquitinate and stabilize ZEB1. Moreover, we found a strong positive correlation between the expression of p-RB (an indicator of CDK4/6 activity), p-USP51 and ZEB1 in metastatic human breast cancer samples. Notably, the high expression of p-RB, p-USP51, and ZEB1 was significantly correlated with a poor clinical outcome. Taken together, our results provide evidence that the CDK4/6-USP51-ZEB1 axis plays a key role in breast cancer metastasis and could be a viable therapeutic target for the treatment of advanced human cancers.
Highlights
Tumor metastasis is responsible for the majority of cancerassociated mortalities.[1,2] It is well established that tumor metastasis results from cancer cells that have left the primary tumor mass and traveled through the body’s highways—the blood and lymphatic vessels—to new sites throughout the body where they can establish new colonies.[3]
The quantitative PCR results showed that the changes in zinc-finger E-box binding homeobox 1 (ZEB1) mRNA levels were not as evident (Supplementary Fig. S1c), which demonstrates that biochanin A predominantly regulates ZEB1 protein stability
We showed that a combined treatment with biochanin A and CHX led to a rapid decrease in ZEB1 protein levels at the indicated time points (Supplementary Fig. S1d), which implies that biochanin A might promote ZEB1 protein degradation
Summary
Tumor metastasis is responsible for the majority of cancerassociated mortalities.[1,2] It is well established that tumor metastasis results from cancer cells that have left the primary tumor mass and traveled through the body’s highways—the blood and lymphatic vessels—to new sites throughout the body where they can establish new colonies.[3]. Various studies have shown that the expression of ZEB1 is regulated by multiple signaling pathways at the transcriptional level, such as transforming growth factor-β (TGFβ), Wnt and Notch.[9,10] For example, the p65 subunit of NF-κB can activate ZEB1 transcription by directly binding to its promoter, which leads to an EMT phenotype in MCF-10A breast epithelial cells.[11] Another recent report by Jin et al demonstrated that the ubiquitin-conjugating enzyme E2 C (UBE2C) functions as an oncogene that promotes EMT in non-small-cell lung cancer (NSCLC) by directly targeting the 5′-UTR of the transcript encoding ZEB1.12 In addition, the expression of ZEB1 is tightly regulated by a variety of microRNAs at the posttranscriptional level.[13,14,15] It has been well established that miR-200 family members (e.g., miR-141, miR-200a and miR-200c) facilitate the degradation of ZEB1 mRNA by directly binding to its 3′-UTR, which results in distinct tumor phenotypes such as stemness and distant metastasis.[15,16,17] only a few studies have focused on the mechanisms of the posttranslational modification of ZEB1. Further elucidating the underlying mechanisms of ZEB1 posttranslational regulation will identify new therapeutic strategies to deplete ZEB1 expression and to overcome metastasis and therapy resistance in human cancers
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