Nuclear TEAD4 with SIX1 Overexpression is an Independent Prognostic Marker in the Stage I–III Colorectal Cancer

Abstract

Introduction

Stage I–III colorectal cancer patients are under risk of tumor recurrence and metachronous metastasis after radical surgery. An increased expression of transcription factor TEAD4 is associated with epithelial-mesenchymal transition, metastasis and poor prognosis in colorectal cancer. However, the mechanistic role of TEAD4 in driving colon cancer progression and its prognostic value in early stage of CRC remains unclear.

Methods

In this study, the regulation, function and prognostic significance of TEAD4 and its new direct target gene SIX1 in CRC progression were evaluated using human tissues, molecular and cell biology.

Results

We show that TEAD4 directly upregulates the expression of SIX1 at transcriptional level in CRC cells, establishing that SIX1 is a new direct target gene of TEAD4. TEAD4 promotes EMT and cell migration of CRC cells, while SIX1 knockdown attenuates this effect and SIX1 overexpression enhances this effect, indicating that SIX1 mediates the function of TEAD4 in promoting cell migration in CRC cells. Clinically, nuclear TEAD4, overexpression of SIX1 and nuclear TEAD4 with SIX1 overexpression predict poor prognosis in CRC patients.

Discussion

Our study identifies TEAD4-SIX1-CDH1 form a novel signaling axis, which contributes to CRC progression, and its aberrant expression and activation predicts poor prognostic for CRC patients in stage I–III.

Keywords:

• colorectal cancer
• TEAD4
• SIX1
• hippo pathway

Acknowledgments

The work was supported in part by grants #81672517, #81570474, #81502020, #82073056, and #82002507 from the National Natural Science Foundation of China, Shanghai Pujiang Program (19PJ1407600) and sponsored by Shanghai Municipal Commission of Health and Family Planning (#201740122).

Disclosure

The authors declare no competing interests.