Capicua suppresses colorectal cancer progression via repression of ETV4 expression

Jeon-Soo Lee,Sanguk Kim,Jongeun Lee,Donghyo Kim,Hyeongjoo Kim,Yoontae Lee,Chang-Jin Kim,Eunjeong Kim,Dongjun Jeong

doi:10.1186/s12935-020-1111-8

Jeon-Soo Lee, Sanguk Kim + Show 7 more

Open Access

https://doi.org/10.1186/s12935-020-1111-8

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Abstract

BackgroundAlthough 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.MethodsDatabases 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.ResultsCIC 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.ConclusionCollectively, 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.

Highlights

Major driver gene mutations have been identified, the complex molecular heterogeneity of colorectal cancer (CRC) remains unclear
We examined the association of CIC and Polyoma enhancer activator 3 (PEA3) group transcription factors with CRC clinicopathology by conducting analyses of the The Cancer Genome Atlas (TCGA) dataset and tissue samples derived from CRC patients
Analyses of the datasets for CRC patients from The Cancer Genome Atlas (TCGA) and Catalogue of Somatic Mutations in Cancer (COSMIC) databases revealed that CIC levels were slightly decreased in the colorectal tumor samples compared with the normal tissues (Fig. 1a and b, Additional file 1: Table S2, and Additional file 2: Fig. S1b)

Summary

Introduction

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; its role in CRC progression has not been examined. Lee et al Cancer Cell Int (2020) 20:42 angiogenesis and the epidermal growth factor receptor (EGFR) pathway, respectively, have been actively developed [8]. These inhibitors cannot be used for the effective treatment of all CRC patients. Through the HMG box and C-terminal domains, CIC recognizes specific octameric DNA sequences (5′-T(G/C)AATG(A/G) (A/G)-3′) to regulate the expression of its target genes [12, 15, 16]. CIC is required for lung alveolarization, liver homeostasis, brain development and function, and immune cell homeostasis [24,25,26,27,28]

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