Jun 14, 2016

A splicing isoform of TEAD4 attenuates the Hippo-YAP signalling to inhibit tumour proliferation

Nature Communications
Yangfan QiZefeng Wang

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.

  • References54
  • Citations18

References

Mentioned in this Paper

Nested Transcripts
Biochemical Pathway
Size
Dominant-Negative Mutation
Cell Proliferation Regulatory Process
Neoplasms
DNAJB1
Tumor Lysis Syndrome
YY1AP1
Cell Nucleus

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