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YAP silencing by RB1 mutation is essential for small-cell lung cancer metastasis

Zhengming Wu1, Junhui Su2, Fu-Long Li3

  • 1Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA, 92093, USA.

Nature Communications
|September 22, 2023
PubMed

Insights

Loss of YAP expression drives small cell lung cancer (SCLC) metastasis. Benzamide HDAC inhibitors restore YAP, suppressing SCLC spread and improving survival in mice.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Metastasis

Background:

  • Small cell lung cancer (SCLC) is characterized by high lethality due to frequent metastasis.
  • Inactivating mutations in TP53 and RB1 are common in SCLC.
  • The molecular mechanisms driving SCLC metastasis remain incompletely understood.

Purpose of the Study:

  • To investigate the role of YAP expression in SCLC metastasis.
  • To elucidate the regulatory mechanisms of YAP transcription in SCLC.
  • To identify potential therapeutic strategies targeting SCLC metastasis.

Main Methods:

  • Analysis of YAP expression in SCLC cells.
  • Investigation of YAP target genes (CCN1/CCN2) and their role in migration.
  • Study of RB1 mutation, E2F7, and RCOR complex interaction with the YAP promoter.
  • Evaluation of benzamide family HDAC inhibitors in vitro and in a mouse model.

Main Results:

  • Loss of YAP expression correlates with increased ameboid migration and metastatic potential in SCLC.
  • YAP inhibits SCLC ameboid migration via CCN1/CCN2.
  • RB1 mutations lead to YAP transcriptional silencing through E2F7 and RCOR recruitment.
  • Benzamide HDAC inhibitors restore YAP expression by targeting the RCOR-HDAC complex, suppressing metastasis, and improving survival in mice.

Conclusions:

  • YAP plays a critical role in suppressing SCLC ameboid migration and metastasis.
  • The E2F7/RCOR/Sin3 HDAC complex mediates YAP transcriptional silencing in RB1-mutated SCLC.
  • Benzamide HDAC inhibitors represent a promising therapeutic strategy for SCLC by restoring YAP expression and inhibiting metastasis.

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