Introduction: Sirtuin 1 (SIRT1) is a key modulator in several types of cancer, including colorectal cancer (CRC). Here, we probed into the molecular mechanism of SIRT1 regulating the development and chemoresistance of CRC.
Methods: Differentially expressed genes related to the growth, metastasis and chemoresistance of CRC were identified by bioinformatics analysis. The expression of SIRT1 in clinical tissues from CRC patients and CRC cell lines was detected by RT-qPCR. Interactions among SIRT1, p53, miR-101 and KPNA3 were analyzed. The effect of SIRT1 on the cell viability, migration, invasion, epithelial-mesenchymal transformation and chemoresistance to 5-FU was evaluated using loss-function investigations in CRC cells. Finally, a xenograft model of CRC and a metastasis model were constructed for further exploration of the roles of SIRT1 in vivo.
Results: SIRT1 was elevated in CRC tissues and cell lines. SIRT1 decreased p53 via deacetylation, and consequently downregulated the expression of miR-101 while increasing that of the miR-101 target gene KPNA3. By this mechanism, SIRT1 enhanced the proliferation, migration, invasion, epithelial-mesenchymal transformation, and resistance to 5-FU of CRC cells. In addition, in vivo data also showed that SIRT1 promoted the growth, metastasis and chemoresistance to 5-FU of CRC cells via regulation of the p53/miR-101/KPNA3 axis.
Conclusions: In conclusion, SIRT1 can function as an oncogene in CRC by accelerating the growth, metastasis and chemoresistance to 5-FU of CRC cells through the p53/miR-101/KPNA3 axis.
Keywords: KPNA3; MiR-101; SIRT1; chemoresistance; colorectal cancer; epithelial-mesenchymal transformation; metastasis; p53.