VGLL2-NCOA2 and TEAD1-NCOA2 fusions recruited p300 to drive TEAD-dependent transcription (CUT&RUN)

The vestigial like family proteins (VGLL) are thought to regulate transcription by interacting with the TEA domain transcription factors (TEAD), the primary mediators of the Hippo pathway. However, the functional regulation of VGLL proteins remains poorly characterized. Here, we explored the molecular mechanism of two VGLL2 and TEAD1 fusion proteins generated by recurrent translocations in spindle cell rhabdomyosarcoma. We demonstrated that, compared to VGLL2 and TEAD1 alone, VGLL2-NCOA2 and TEAD1-NCOA2 act as strong transcriptional activators of TEAD-mediated transcription. Although VGLL2-NCOA2 and Yes1 associated transcriptional regulator (YAP) control overlapping transcriptional programs and chromatin landscapes, the downstream transcription induced by the fusion proteins does not require YAP and WW domain containing transcription regulator 1 (TAZ). Furthermore, VGLL2-NCOA2 and TEAD1-NCOA2 fusions engage distinct epigenetic regulation by recruiting E1A binding protein p300 (p300) to drive TEAD-dependent transcription. We showed that small molecule p300 inhibition can suppress VGLL2-NCOA2 and TEAD1-NCOA2-induced oncogenic transformation both in vitro and in vivo. Overall, our data reveal a tumorigenic mechanism of VGLL and TEAD fusion proteins that is related to the Hippo pathway but independent of YAP/TAZ, suggesting potential therapeutic strategies for tumors carrying VGLL, TEAD, or nuclear receptor coactivator (NCOA) gene rearrangements.