RRC ID 52695
Author Huang CK, Iwagami Y, Zou J, Casulli S, Lu S, Nagaoka K, Ji C, Ogawa K, Cao KY, Gao JS, Carlson RI, Wands JR.
Title Aspartate beta-hydroxylase promotes cholangiocarcinoma progression by modulating RB1 phosphorylation.
Journal Cancer Lett.
Abstract Cholangiocarcinoma (CCA) is a highly lethal and aggressive disease. Recently, IDH1/2 mutations have been identified in approximately 20% of CCAs which suggests an involvement of 2-oxoglutarate (2-OG) -dependent dioxygenases in oncogenesis. We investigated if the 2-OG dependent dioxygenase, aspartate beta-hydroxylase (ASPH) was important in tumor development and growth. Immunoassays were used to clarify how ASPH modulates CCA progression by promoting phosphorylation of the retinoblastoma protein (RB1). A xenograft model was employed to determine the role of ASPH on CCA growth. Knockdown of ASPH expression inhibited CCA development and growth by reducing RB1 phosphorylation. Expression of ASPH promoted direct protein interaction between RB1, cyclin-dependent kinases, and cyclins. Treatment with 2-OG-dependent dioxygenase and ASPH inhibitors suppressed the interaction between RB1 and CDK4 as well as RB1 phosphorylation. Knockdown of ASPH expression inhibited CCA progression and RB1 phosphorylation in vivo and they were found to be highly expressed in human CCAs. Knockdown of ASPH expression altered CCA development by modulating RB1 phosphorylation, as one of the major factors regulating the growth of these tumors.
Volume 429
Pages 1-10
Published 2018-8-10
DOI 10.1016/j.canlet.2018.04.041
PII S0304-3835(18)30316-1
PMID 29733964
PMC PMC5985220
MeSH Animals Bile Duct Neoplasms / genetics Bile Duct Neoplasms / metabolism* Bile Duct Neoplasms / therapy Calcium-Binding Proteins / genetics Calcium-Binding Proteins / metabolism* Cell Line, Tumor Cholangiocarcinoma / enzymology* Cholangiocarcinoma / genetics Cholangiocarcinoma / therapy Disease Progression Female Humans Membrane Proteins / genetics Membrane Proteins / metabolism* Mice, Knockout Mice, Nude Mixed Function Oxygenases / genetics Mixed Function Oxygenases / metabolism* Muscle Proteins / genetics Muscle Proteins / metabolism* Phosphorylation Protein Binding RNA Interference RNAi Therapeutics / methods Retinoblastoma Protein / genetics Retinoblastoma Protein / metabolism* Xenograft Model Antitumor Assays / methods
IF 6.508
Resource
Human and Animal Cells TFK-1(RCB2537)