Journal
CELL DEATH & DISEASE
Volume 12, Issue 5, Pages -Publisher
SPRINGERNATURE
DOI: 10.1038/s41419-021-03780-y
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Funding
- National Key R&D Project of China [2019YFC1711000, 2019YFC1708902, 2018ZX09711001-008-003]
- National Natural Science Foundation [81973505, 81773932, 82030114]
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SDC4 functions as a key therapeutic target in HCC, and small-molecule bufalin can inhibit HCC proliferation and migration by regulating the SDC4/DDX23 signaling axis.
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.
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