Rac GTPase activating protein 1 promotes gallbladder cancer via binding DNA ligase 3 to reduce apoptosis

Rui Bian; Wei Dang; Xiaoling Song; Liguo Liu; Chengkai Jiang; Yang Yang; Yongsheng Li; Lin Li; Xuechuan Li; Yunping Hu; Runfa Bao; Yingbin Liu

doi:10.7150/ijbs.58857

Rac GTPase activating protein 1 promotes gallbladder cancer via binding DNA ligase 3 to reduce apoptosis

Int J Biol Sci. 2021 May 27;17(9):2167-2180. doi: 10.7150/ijbs.58857. eCollection 2021.

Authors

Rui Bian^{1

2

3}, Wei Dang^{4

2

3}, Xiaoling Song^{4

2

3}, Liguo Liu^{1

2

3}, Chengkai Jiang^{1

2

3}, Yang Yang^{1

2

3}, Yongsheng Li^{1

2

3}, Lin Li^{1

2

3}, Xuechuan Li^{1

2

3}, Yunping Hu^{4

2

3}, Runfa Bao^{4

2

3}, Yingbin Liu^{1

2

3}

Affiliations

¹ Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
² Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai 200092, China.
³ State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200240, China.
⁴ Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200092, China.

Abstract

Rac GTPase activating protein 1 (RACGAP1) has been characterized in the pathogenesis and progression of several malignancies, however, little is known regarding its role in the development of gallbladder cancer (GBC). This investigation seeks to describe the role of RACGAP1 and its associated molecular mechanisms in GBC. It was found that RACGAP1 was highly expressed in human GBC tissues, which was associated to poorer overall survival (OS). Gene knockdown of RACGAP1 hindered tumor cell proliferation and survival both in vitro and in vivo. We further identified that RACGAP1 was involved in DNA repair through its binding with DNA ligase 3 (LIG3), a crucial component of the alternative-non-homologous end joining (Alt-NHEJ) pathway. RACGAP1 regulated LIG3 expression independent of RhoA activity. RACGAP1 knockdown resulted in LIG3-dependent repair dysfunction, accumulated DNA damage and Poly(ADP-ribosyl) modification (PARylation) enhancement, leading to increased apoptosis and suppressed cell growth. We conclude that RACGAP1 exerts a tumor-promoting role via binding LIG3 to reduce apoptosis and facilitate cell growth in GBC, pointing to RACGAP1 as a potential therapeutic target for GBC.

Keywords: DNA damage repair; LIG3; RACGAP1; apoptosis; gallbladder cancer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis / genetics*
Cell Proliferation / genetics
DNA Ligase ATP / genetics
DNA Ligase ATP / metabolism*
Female
GTPase-Activating Proteins / genetics
GTPase-Activating Proteins / metabolism*
Gallbladder Neoplasms / genetics
Gallbladder Neoplasms / metabolism*
Gallbladder Neoplasms / pathology
Gene Expression Regulation, Neoplastic
Gene Knockdown Techniques
Humans
Male
Mice
Mice, Nude
Middle Aged
Poly-ADP-Ribose Binding Proteins / genetics
Poly-ADP-Ribose Binding Proteins / metabolism*
Survival Rate
Xenograft Model Antitumor Assays
rhoA GTP-Binding Protein / genetics
rhoA GTP-Binding Protein / metabolism

Substances

GTPase-Activating Proteins
Poly-ADP-Ribose Binding Proteins
mgcRacGAP
RHOA protein, human
rhoA GTP-Binding Protein
DNA Ligase ATP
LIG3 protein, human