UBIAD1 suppresses the proliferation of bladder carcinoma cells by regulating H-Ras intracellular trafficking via interaction with the C-terminal domain of H-Ras

Zhiliang Xu; Fengsen Duan; Huiai Lu; Maytham Abdulkadhim Dragh; Yanzhi Xia; Huageng Liang; Ling Hong

doi:10.1038/s41419-018-1215-4

UBIAD1 suppresses the proliferation of bladder carcinoma cells by regulating H-Ras intracellular trafficking via interaction with the C-terminal domain of H-Ras

Cell Death Dis. 2018 Dec 5;9(12):1170. doi: 10.1038/s41419-018-1215-4.

Authors

Zhiliang Xu¹, Fengsen Duan¹, Huiai Lu¹, Maytham Abdulkadhim Dragh¹, Yanzhi Xia¹, Huageng Liang², Ling Hong³

Affiliations

¹ Department of Genetics and Developmental Biology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China.
² Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China.
³ Department of Genetics and Developmental Biology, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China. lhong@mail.hust.edu.cn.

Abstract

UbiA prenyltransferase domain-containing protein 1 (UBIAD1) plays a key role in biosynthesis of vitamin K₂ and coenzyme Q10 using geranylgeranyl diphosphate (GGPP). However, the mechanism by which UBIAD1 participates in tumorigenesis remains unknown. This study show that UBIAD1 interacts with H-Ras, retains H-Ras in the Golgi apparatus, prevents H-Ras trafficking from the Golgi apparatus to the plasma membrane, blocks the aberrant activation of Ras/MAPK signaling, and inhibits the proliferation of bladder cancer cells. In addition, GGPP was required to maintain the function of UBIAD1 in regulating the Ras/ERK signaling pathway. A Drosophila model was employed to confirm the function of UBIAD1/HEIX in vivo. The activation of Ras/ERK signaling at the plasma membrane induced melanotic masses in Drosophila larvae. Our study suggests that UBIAD1 serves as a tumor suppressor in cancer and tentatively reveals the underlying mechanism of melanotic mass formation in Drosophila.

Publication types

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

MeSH terms

Animals
Cell Line, Tumor
Cell Membrane / drug effects
Cell Membrane / metabolism
Cell Membrane / ultrastructure
Cell Proliferation / drug effects
Dimethylallyltranstransferase / chemistry
Dimethylallyltranstransferase / genetics*
Dimethylallyltranstransferase / metabolism
Drosophila Proteins / genetics*
Drosophila Proteins / metabolism
Drosophila melanogaster / cytology
Drosophila melanogaster / metabolism
Epithelial Cells / drug effects
Epithelial Cells / metabolism*
Epithelial Cells / pathology
Gene Expression Regulation, Neoplastic*
Genes, Reporter
Golgi Apparatus / drug effects
Golgi Apparatus / metabolism*
Golgi Apparatus / ultrastructure
Green Fluorescent Proteins / genetics
Green Fluorescent Proteins / metabolism
HEK293 Cells
Humans
Larva / cytology
Larva / metabolism
Luminescent Proteins / genetics
Luminescent Proteins / metabolism
Plasmids / chemistry
Plasmids / metabolism
Polyisoprenyl Phosphates / pharmacology
Protein Binding
Protein Domains
Protein Transport / drug effects
Proto-Oncogene Proteins p21(ras) / chemistry
Proto-Oncogene Proteins p21(ras) / genetics*
Proto-Oncogene Proteins p21(ras) / metabolism
Red Fluorescent Protein
Signal Transduction
Transfection

Substances

Drosophila Proteins
Luminescent Proteins
Polyisoprenyl Phosphates
enhanced green fluorescent protein
heix protein, Drosophila
Green Fluorescent Proteins
Dimethylallyltranstransferase
UBIAD1 protein, human
HRAS protein, human
Proto-Oncogene Proteins p21(ras)
geranylgeranyl pyrophosphate