SAMD4 represses VGLL4 mRNA to activate TEAD and promote cancer progression

The transcriptional cofactors YAP1 and TAZ regulate target gene expression by binding to the transcription factor TEAD. Due to their roles in cancer initiation, progression, and drug resistance, YAP1 and TAZ are promising targets for cancer therapy. SAMD4A/B are RNA-binding proteins that are broadly expressed across human tissues, but few of their molecular targets and biological functions have been identified. In Drosophila, the SAMD4A/B homolog Smaug participates in early embryonic development by disrupting the stability and translation of maternal mRNA. To discover targets inhibiting the YAP1/TAZ-TEAD oncogenic transcription program, we screened a whole-genome siRNA library and identified siSAMD4B as potently suppressing TEAD activity in human cancer cells. We showed that SAMD4A/B increased TEAD activity by destabilizing and repressing the translation of VGLL4 mRNA, promoting cancer progression in vitro. Conversely, inhibiting either SAMD4A or SAMD4B elevated VGLL4 mRNA, which suppressed TEAD activity and inhibited cancer progression. Notably, transgenic mice expressing liver-specific SAMD4B exhibited accelerated development of intrahepatic cholangiocarcinomas in an Nf2-deficient background. These tumors appeared in the mutants at one week of age and caused death due to hepatic failure by 100 days. Thus, SAMD4A/B may be a promising target for anticancer drugs designed to inhibit TEAD activation.