Cell Death and Disease (May 2021)

Therapeutic potential of targeting membrane-spanning proteoglycan SDC4 in hepatocellular carcinoma

  • Heng Yang,
  • Yang Liu,
  • Mei-Mei Zhao,
  • Qiang Guo,
  • Xi-Kang Zheng,
  • Dan Liu,
  • Ke-Wu Zeng,
  • Peng-Fei Tu

DOI
https://doi.org/10.1038/s41419-021-03780-y
Journal volume & issue
Vol. 12, no. 5
pp. 1 – 16

Abstract

Read online

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.