Abstract

Syndecan-4 (SDC4) functions as a major endogenous membrane-associated receptor and widely regulates cytoskeleton, cell adhesion, and cell migration in human tumorigenesis and development, which represents a charming anti-cancer therapeutic target. Here, SDC4 was identified as a direct cellular target of small-molecule bufalin with anti-hepatocellular carcinoma (HCC) activity. Mechanism studies revealed that bufalin directly bond to SDC4 and selectively increased SDC4 interaction with substrate protein DEAD-box helicase 23 (DDX23) to induce HCC genomic instability. Meanwhile, pharmacological promotion of SDC4/DDX23 complex formation also inactivated matrix metalloproteinases (MMPs) and augmented p38/JNK MAPKs phosphorylation, which are highly associated with HCC proliferation and migration. Notably, specific knockdown of SDC4 or DDX23 markedly abolished bufalin-dependent inhibition of HCC proliferation and migration, indicating SDC4/DDX23 signaling axis is highly involved in the HCC process. Our results indicate that membrane-spanning proteoglycan SDC4 is a promising druggable target for HCC, and pharmacological regulation of SDC4/DDX23 signaling axis with small-molecule holds great potential to benefit HCC patients.

Details

Title
Therapeutic potential of targeting membrane-spanning proteoglycan SDC4 in hepatocellular carcinoma
Author
Yang, Heng 1 ; Liu, Yang 1 ; Mei-Mei, Zhao 1 ; Guo, Qiang 1 ; Xi-Kang, Zheng 1 ; Liu, Dan 2 ; Ke-Wu, Zeng 1   VIAFID ORCID Logo  ; Peng-Fei, Tu 1 

1  Peking University, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Beijing, China (GRID:grid.11135.37) (ISNI:0000 0001 2256 9319) 
2  Peking University Health Science Center, Proteomics Laboratory, Medical and Healthy Analytical Center, Beijing, China (GRID:grid.11135.37) (ISNI:0000 0001 2256 9319) 
Publication year
2021
Publication date
May 2021
Publisher
Springer Nature B.V.
e-ISSN
20414889
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41419-021-03780-y
ProQuest document ID
2527360004
Copyright
© The Author(s) 2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.