Gene regulatory network analysis identifies master regulators for reverting colorectal cancer cells into normal-like gene expression state

Abstract

Colorectal cancer (CRC) is known to occur through the accumulation of sequential mutations over long periods of time. Because of the high incidence and mortality of CRC, the importance of early diagnosis and treatment has been highlighted. Therefore, it is essential to understand molecular regulatory mechanisms of tumorigenesis in the CRC. In this study, we attempted to identify a master regulator that reverts abnormal gene expression state in CRC to normal gene expression profile. To identify the master regulator of CRC, we reconstructed cancer-specific gene regulatory network (GRN) from CRC patients’ gene expression data. As a result of master regulator analysis (MRA) using GRN, we selected TEAD4 with increased gene expression level and protein activity in adenoma as the master regulator of tumorigenesis. We verified the effect of TEAD4 knockdown (KD) in APC-deleted human colonic epithelial cells (HCEC-1CT-A), a model of CRC development. The results showed that the gene expression profile of HCEC-1CT-A was transformed into normal HCEC-1CT by decreasing proliferation and inducing cell differentiation. However, TEAD4 alone only inhibits cell proliferation in CRC that additional mutations were accumulated. Therefore, in this paper, we suggest ELK1 as a combination target of reverting CRC to normal-like differentiated cells discovered through network analysis.