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bioRxiv · 10.1101/2024.05.01.592016

VGLL2 and TEAD1 fusion proteins drive YAP/TAZ-independent transcription and tumorigenesis by engaging p300

Guo, S.·Hu, X.·Cotton, J. L.·Ma, L.·Li, Q.·Cui, J.·Wang, Y.·Thakare, R. P.·Tao, Z.·Ip, T.·Wu, X.·Wang, J.·Mao, J.
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Abstract

Studies on Hippo pathway regulation of tumorigenesis largely center on YAP and TAZ, the transcriptional co-regulators of TEAD. Here, we present an oncogenic mechanism involving VGLL and TEAD fusions that is Hippo pathway-related but YAP/TAZ-independent. We characterize two recurrent fusions, VGLL2-NCOA2 and TEAD1-NCOA2, recently identified in spindle cell rhabdomyosarcoma. We demonstrate that in contrast to VGLL2 and TEAD1, the fusion proteins are strong activators of TEAD-dependent transcription, and their function does not require YAP/TAZ. Furthermore, we identify that VGLL2 and TEAD1 fusions engage specific epigenetic regulation by recruiting histone acetyltransferase p300 to control TEAD-mediated transcriptional and epigenetic landscapes. We showed that small molecule p300 inhibition can suppress fusion proteins-induced oncogenic transformation both in vitro and in vivo. Overall, our study reveals a molecular basis for VGLL involvement in cancer and provides a framework for targeting tumors carrying VGLL, TEAD, or NCOA translocations.

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Guo, S., Hu, X., Cotton, J. L., Ma, L., Li, Q., Cui, J., Wang, Y., Thakare, R. P., Tao, Z., Ip, T., Wu, X., Wang, J., Mao, J.. 2024-05-03. VGLL2 and TEAD1 fusion proteins drive YAP/TAZ-independent transcription and tumorigenesis by engaging p300. https://doi.org/10.1101/2024.05.01.592016

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