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Published on: July 12, 2018
Therapeutic potential of targeting membrane-spanning proteoglycan SDC4 in hepatocellular carcinoma
Heng Yang1, Yang Liu1, Mei-Mei Zhao1
1State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China.
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.
Insights
Small-molecule bufalin targets Syndecan-4 (SDC4) to inhibit hepatocellular carcinoma (HCC) by disrupting the SDC4/DDX23 complex. This discovery offers a new therapeutic strategy for HCC patients.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Syndecan-4 (SDC4) is a key regulator of cellular processes implicated in human tumorigenesis.
- SDC4's role in hepatocellular carcinoma (HCC) presents a potential therapeutic target.
Purpose of the Study:
- To identify the direct cellular target of bufalin, a small molecule with anti-HCC activity.
- To elucidate the molecular mechanisms by which bufalin inhibits HCC progression.
Main Methods:
- Direct binding assays to confirm bufalin-SDC4 interaction.
- Analysis of SDC4 interaction with DEAD-box helicase 23 (DDX23).
- Assessment of downstream effects on matrix metalloproteinases (MMPs) and MAPK signaling.
- Gene knockdown studies to validate the role of SDC4/DDX23 axis.
Main Results:
- Bufalin directly binds to SDC4, enhancing its interaction with DDX23.
- This interaction induces genomic instability and inactivates MMPs in HCC cells.
- Bufalin treatment augmented p38/JNK MAPKs phosphorylation, inhibiting HCC proliferation and migration.
- Knockdown of SDC4 or DDX23 abrogated bufalin's anti-cancer effects.
Conclusions:
- SDC4 is a druggable target in HCC.
- The SDC4/DDX23 signaling axis is crucial for HCC progression.
- Targeting the SDC4/DDX23 axis with small molecules like bufalin shows therapeutic potential for HCC patients.
