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Background  Although major driver gene mutations have been identified, the complex molecular heterogeneity of colorectal cancer (CRC) remains unclear. Capicua (CIC) functions as a tumor suppressor in various types of cancers; however, its role in CRC progression has not been examined.    Methods  Databases for gene expression profile in CRC patient samples were used to evaluate the association of the levels of  CIC  and  Polyoma enhancer activator 3  ( PEA3 ) group genes ( ETS translocation variant 1  ( ETV1 ),  ETV4 , and  ETV5 ), the best-characterized CIC targets in terms of CIC functions, with clinicopathological features of CRC. CIC and ETV4 protein levels were also examined in CRC patient tissue samples. Gain- and loss-of function experiments in cell lines and mouse xenograft models were performed to investigate regulatory functions of CIC and ETV4 in CRC cell growth and invasion. qRT-PCR and western blot analyses were performed to verify the CIC regulation of ETV4 expression in CRC cells. Rescue experiments were conducted using siRNA against  ETV4  and CIC-deficient CRC cell lines.    Results  CIC expression was decreased in the tissue samples of CRC patients. Cell invasion, migration, and proliferation were enhanced in CIC-deficient CRC cells and suppressed in CIC-overexpressing cells. Among  PEA3  group genes,  ETV4  levels were most dramatically upregulated and inversely correlated with the CIC levels in CRC patient samples. Furthermore, derepression of  ETV4  was more prominent in CIC-deficient CRC cells, when compared with that observed for  ETV1  and  ETV5 . The enhanced cell proliferative and invasive capabilities in CIC-deficient CRC cells were completely recovered by knockdown of  ETV4 .    Conclusion  Collectively, the CIC-ETV4 axis is not only a key module that controls CRC progression but also a novel therapeutic and/or diagnostic target for CRC.

Capicua suppresses colorectal cancer progression via repression of ETV4 expression