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The actin-binding protein drebrin disrupts NF2-LATS kinases complex assembly to facilitate liver tumorigenesis

Yang Sun1, Henan Wei2, Wentao Yu2

  • 1Sheng Yushou Center of Cell Biology and Immunology, Department of Genetics and Developmental Science, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Minghang, Shanghai, China.

Hepatology (Baltimore, Md.)
|September 26, 2024
PubMed
Abstract

Insights

Drebrin (DBN1) disrupts Hippo signaling by interacting with Neurofibromin 2 (NF2), inhibiting tumor growth. Inhibiting DBN1 shows promise for cancer therapy by restoring NF2 function.

Area of Science:

  • Cell biology
  • Molecular oncology
  • Signal transduction

Background:

  • The Hippo signaling pathway is vital for maintaining tissue homeostasis and is implicated in cancer development.
  • Neurofibromin 2 (NF2) is a key component of Hippo signaling and is linked to human cancers, yet it remains an under-explored therapeutic target.
  • Understanding novel regulators of Hippo signaling is crucial for developing effective cancer treatments.

Purpose of the Study:

  • To identify novel modulators of Hippo signaling pathway components, specifically focusing on Neurofibromin 2 (NF2).
  • To investigate the role of Drebrin (DBN1) in regulating YAP localization and its interaction with NF2.
  • To explore the therapeutic potential of targeting the DBN1-NF2 interaction in cancer, particularly hepatocellular carcinoma (HCC).

Main Methods:

  • Genome-wide RNA interference screen to identify modulators of YAP localization.
  • Biochemical assays to confirm DBN1 interaction with NF2 and its effect on LATS kinase activation.
  • In vitro and in vivo studies using DBN1 mutants and a DBN1 inhibitor (BTP2) to assess effects on tumorigenesis.
  • Combination therapy studies with sorafenib and BTP2 in HCC models.

Main Results:

  • Drebrin (DBN1) was identified as a novel regulator of YAP localization, directly interacting with NF2.
  • DBN1 binding disrupts NF2 interaction with LATS kinases, leading to YAP activation and promoting liver tumorigenesis.
  • A DBN1 mutant (DBN1-3K mut) defective in NF2 binding inhibited YAP activation and tumorigenesis.
  • Pharmacological inhibition of DBN1 with BTP2 restored NF2-LATS binding and demonstrated antitumor activity, synergizing with sorafenib in HCC.

Conclusions:

  • A novel DBN1-NF2-LATS signaling axis regulating Hippo pathway activity in cancer was identified.
  • Pharmacological inhibition of DBN1 represents a promising therapeutic strategy targeting the Hippo pathway for cancer treatment.
  • Targeting DBN1 offers a new avenue for intervention in cancers driven by dysregulated Hippo signaling.

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