DSTN hypomethylation promotes radiotherapy resistance of rectal cancer by activating Wnt/β-catenin signaling pathway

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Abstract Background Although surgical resection combined with neoadjuvant radiotherapy can reduce the local recurrence rate of rectal cancer, only some patients benefit from neoadjuvant radiotherapy. Therefore, how to screen out rectal cancer patients who are sensitive or resistant to radiotherapy has great clinical significance. Results We found that DSTN was highly expressed (P <0.05) and hypomethylated (P <0.01) in neoadjuvant radiotherapy resistant tissues of rectal cancer. Follow-up data confirmed that patients with high expression of DSTNin neoadjuvant radiotherapy resistant tissues of rectal cancer had a shorter disease-free survival (P <0.05). DSTNexpression increased after methyltransferase inhibitor inhibited DNA methylation in DNA promoter region of colorectal cancer cells (P <0.05). In vitro and in vivo experiments showed that knockdown of DSTN could promote the sensitivity of colorectal cancer cells to radiotherapy, and overexpression of DSTNcould promote the resistance of colorectal cancer cells to radiation (P <0.05). The expression of C-Myc and Cyclin D1, which are downstream of Wnt/β-catenin signaling pathway, were up-regulated in colorectal cancer cells with overexpression of DSTN. The expression of β-catenin was highly expressed in radiotherapy resistant tissues, and there was a linear correlation between the expression of DSTN and β-catenin (P <0.0001). Further studies showed that DSTNcould bind to β-catenin and increase the stability of β-catenin. Conclusion The degree of DNA methylation and the expression level of DSTN can be used as a biomarker to predict the sensitivity of neoadjuvant radiotherapy for rectal cancer, and DSTN and β-catenin are also expected to become a reference and a new target for the selection of neoadjuvant radiotherapy for rectal cancer.

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