Abstract
Aberrant splicing is frequently found in cancer, yet the biological consequences of such alterations are mostly undefined. Here we report that the Hippo–YAP signalling, a key pathway that regulates cell proliferation and organ size, is under control of a splicing switch. We show that TEAD4, the transcription factor that mediates Hippo–YAP signalling, undergoes alternative splicing facilitated by the tumour suppressor RBM4, producing a truncated isoform, TEAD4-S, which lacks an N-terminal DNA-binding domain, but maintains YAP interaction domain. TEAD4-S is located in both the nucleus and cytoplasm, acting as a dominant negative isoform to YAP activity. Consistently, TEAD4-S is reduced in cancer cells, and its re-expression suppresses cancer cell proliferation and migration, inhibiting tumour growth in xenograft mouse models. Furthermore, TEAD4-S is reduced in human cancers, and patients with elevated TEAD4-S levels have improved survival. Altogether, these data reveal a splicing switch that serves to fine tune the Hippo–YAP pathway.
Highlights
Aberrant splicing is frequently found in cancer, yet the biological consequences of such alterations are mostly undefined
The transcription factor-mediating YAP-dependent gene expression, TEAD4, contains two functional domains: an N-terminal domain recognizing the enhancer of targeted genes through direct binding of DNA and a C-terminal motif that interacts with transcription co-activator YAP to promote transcription of target genes[33]
On the basis of the annotation of the RNA sequencing (RNA-seq) data, we discovered that the exon 3 of human TEAD4 can be skipped to generate a new isoform, producing a truncated TEAD4 protein with an alternative start site at exon 6
Summary
Aberrant splicing is frequently found in cancer, yet the biological consequences of such alterations are mostly undefined. We show that TEAD4, the transcription factor that mediates Hippo–YAP signalling, undergoes alternative splicing facilitated by the tumour suppressor RBM4, producing a truncated isoform, TEAD4-S, which lacks an N-terminal DNA-binding domain, but maintains YAP interaction domain. We report that the Hippo pathway is under control of a new splicing switch in TEAD4, producing a truncated isoform, TEAD4-S, which lacks an N-terminal DNA-binding domain, but maintains YAP interaction domain. TEAD4-S is reduced in human cancers, and patients with elevated TEAD4-S levels have improved survival These data reveal a splicing switch that serves to fine tune the Hippo–YAP pathway. We expect that splicing misregulations of other genes in the Hippo–YAP pathway play critical roles in cancer development and should be explored as new route of potential cancer therapy
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