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SAMD4 represses VGLL4 mRNA to activate TEAD and promote cancer progression

Junji Otani1,2, Miki Nishio1, Riko Tokita1

  • 1Division of Molecular and Cellular Biology, Kobe University Graduate School of Medicine, Kobe, Japan.

Oncogene
|April 21, 2026
PubMed

Insights

SAMD4A/B proteins promote cancer by destabilizing VGLL4 mRNA, which activates YAP1/TAZ-TEAD transcription. Inhibiting SAMD4A/B boosts VGLL4, suppressing cancer progression and TEAD activity.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Genetics

Background:

  • YAP1 and TAZ are transcriptional cofactors that bind TEAD, driving cancer initiation, progression, and drug resistance.
  • SAMD4A/B are RNA-binding proteins with largely unknown functions; their Drosophila homolog Smaug affects mRNA stability and translation.
  • The YAP1/TAZ-TEAD pathway is a critical therapeutic target in oncology.

Purpose of the Study:

  • To identify novel targets that inhibit the YAP1/TAZ-TEAD oncogenic transcription program.
  • To investigate the role of SAMD4A/B proteins in regulating YAP1/TAZ-TEAD activity and cancer progression.

Main Methods:

  • Whole-genome siRNA library screening to identify suppressors of TEAD activity.
  • Assessing the impact of SAMD4A/B on VGLL4 mRNA stability and translation.
  • In vitro cell-based assays for cancer progression.
  • In vivo studies using transgenic mice with liver-specific SAMD4B expression.

Main Results:

  • siSAMD4B potently suppressed TEAD activity in human cancer cells.
  • SAMD4A/B destabilize and repress VGLL4 mRNA translation, thereby promoting cancer progression.
  • Inhibition of SAMD4A/B increased VGLL4 mRNA, suppressed TEAD activity, and inhibited cancer progression.
  • Liver-specific SAMD4B expression accelerated intrahepatic cholangiocarcinoma development in Nf2-deficient mice.

Conclusions:

  • SAMD4A/B promote cancer progression by negatively regulating VGLL4 mRNA, leading to YAP1/TAZ-TEAD pathway activation.
  • SAMD4A/B represent a promising therapeutic target for developing anticancer drugs that inhibit TEAD activation.

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