CHD4 mediates proliferation and migration of non-small cell lung cancer via the RhoA/ROCK pathway by regulating PHF5A

Nuo Xu,Meiling Zhang,Jian Zhou,Lin Tong,Yuanlin Song,Shengdi Wu,Chunxue Bai,Fanglei Liu,Maosong Ye,Haiyan Ge

doi:10.1186/s12885-020-06762-z

Abstract

BackgroundChromodomain helicase DNA-binding protein 4 (CHD4) has been shown to contribute to DNA repair and cell cycle promotion; however, its roles in cancer initiation and progression remain largely unknown. This study aimed to demonstrate the role of CHD4 in the development of non-small cell lung cancer (NSCLC) and determine the potential mechanisms of action.MethodsBy using immunohistochemistry, the expression levels were evaluated in both cancer and non-cancerous tissues. Subsequently, CHD4 knockdown and overexpression strategies were employed to investigate the effects of CHD4 on cell proliferation, migration, along with the growth and formation of tumors in a xenografts mouse model. The protein expression levels of CHD4, PHF5A and ROCK/RhoA markers were determined by Western blot analysis.ResultsCompared with non-cancerous tissues, CHD4 was overexpressed in cancer tissues and CHD4 expression levels were closely related to clinical parameters of NSCLC patients. In H292 and PC-9 cell lines, CHD4 overexpression could promote the proliferative and migratory potential of NSCLC cells. Furthermore, down-regulation of CHD4 could reduce the proliferative and migratory ability in A549 and H1299 cell lines. Meanwhile, knockdown of CHD4 could decrease the tumorigenicity in nude mice. Finally, we demonstrated that one of the mechanisms underlying the promotive effect of CHD4 on NSCLC proliferation and migration may be through its interaction with PHD finger protein 5A (PHF5A) and subsequent activation of the RhoA/ROCK signaling pathway.ConclusionsCHD4, which is highly expressed in cancer tissue, could be an independent prognostic factor for NSCLC patients. CHD4 plays an important role in regulating the proliferative and migratory abilities of NSCLC via likely the RhoA/ROCK pathway by regulating PHF5A.

Highlights

Chromodomain helicase DNA-binding protein 4 (CHD4) has been shown to contribute to DNA repair and cell cycle promotion; its roles in cancer initiation and progression remain largely unknown
Sims et al demonstrated that depletion of the catalytic ATPase subunit of CHD4 in cells with a dampened DNA damage response (DDR) resulted in a slowgrowth phenotype characterized by a delayed progression through S phase [6]
Identification of CHD4 as an non-small cell lung cancer (NSCLC)-associated gene and correlation of CHD4 expression with NSCLC clinicopathological features To discover whether CHD4 plays an important role in NSCLC, we examined CHD4 expression in 146 paired NSCLC and adjacent non-cancerous tissues (Fig. 1a)

Summary

Introduction

Chromodomain helicase DNA-binding protein 4 (CHD4) has been shown to contribute to DNA repair and cell cycle promotion; its roles in cancer initiation and progression remain largely unknown. This study aimed to demonstrate the role of CHD4 in the development of non-small cell lung cancer (NSCLC) and determine the potential mechanisms of action. Wang et al has found that TRPS1 and CHD4/NuRD formed complex and play a role in cancer cell migration and invasion by repressing TP63 expression in breast and kidney cancer cells [7]. In a recent study, CHD4 was found to be one of the tumor suppressing TF (transcriptional factor) in lung cancer. We investigated the role of CHD4 in the growth and migration of NSCLC using suppression and overexpression strategies in vitro and in vivo

Objectives

Methods

Results

Conclusion