# Upstream regulation of TAZ and YAP in sarcomas: Towards combinatorial therapytargeting the Hippo pathway

> **NIH VA I01** · IOWA CITY VA MEDICAL CENTER · 2024 · —

## Abstract

Sarcomas are cancers arising within bone and soft tissue which rank among the most difficult cancers to treat.
Limb-salvage therapy has reduced the incidence of disfiguring amputations, however many sarcomas involve
crucial anatomical structures precluding this approach. Additionally, five year survival for metastatic sarcomas
is only 16%, underscoring the need for new therapeutic targets. The Hippo pathway is a highly conserved
serine/threonine kinase cascade which negatively regulates the TAZ and YAP transcriptional coactivators. TAZ
and YAP have emerged as important oncogenes in a number of cancers including breast, colon, liver, lung,
pancreas, and thyroid cancers. We have shown that TAZ/YAP are activated in the majority of sarcomas (66%),
however upstream mechanisms regulating TAZ and YAP are poorly understood, representing a significant gap
in knowledge. Our objective in this proposal is to dissect the signal transduction cascades that activate TAZ
and YAP in sarcomas. Our central hypothesis is that histone deacetylation of the regulatory regions of the core
Hippo kinases and MAP4 kinases works in tandem with PI3 kinase signaling to activate TAZ/YAP. This
hypothesis is supported by studies showing that loss of expression of the Hippo kinases is common in both
sarcoma clinical samples and cell lines as well as pharmacological studies showing that inhibition of histone
deacetylases (HDACs) lead to reconstitution of the Hippo kinases thus inhibiting TAZ/YAP. A parallel set of
studies utilizing genetically engineered and xenograft mouse models and sarcoma cell lines have shown that
TAZ and YAP differentially mediate PI3 kinase signaling in undifferentiated pleomorphic sarcoma and pediatric
rhabdomyosarcomas. We plan to test our central hypothesis with the following specific aims:
Aim 1) Identify how TAZ and YAP differentially contribute to PI3 kinase-mediated sarcomagenesis.
We will stimulate PI3K signaling in rhabdomyosarcoma cell lines that are wild-type, TAZ knockout, YAP
knockout, and TAZ/YAP knockout and determine how TAZ and YAP differentially contribute to the PI3 kinase
transcriptome by RNA-Seq gene expression analysis. We will also stimulate PI3K signaling in the muscle of
sarcoma-prone mice that are Trp53fl/flPtenfl/fl and that are Tazfl/flYapfl/fl, Tazfl/fl, Yapfl/fl, or Taz/Yap wild type and
compare tumor latency and gene expression profiles.
Aim 2) Determine if histone deacetylation of MST1/2 and the MAP4 kinases activates TAZ and YAP.
We will inhibit HDACs and assess occupancy of H3K27ac at promoter/enhancer regions of MST1/2 and the
MAP4 kinases (MM kinases) in rhabdomyosarcoma cell lines. To test the importance of the MM kinases in
tumor progression in vivo, we will delete genes encoding the LATS1/2 kinases (that are downstream of the MM
kinases) in sarcoma-prone mice. To achieve this we will inject Trp53fl/fl mice that are Lats1fl/flLats2fl/fl or are
Lats1/Lats2 wild-type with intramuscular adeno-Cre virus.
Aim 3) Determine if ...

## Key facts

- **NIH application ID:** 10881747
- **Project number:** 5I01BX003644-07
- **Recipient organization:** IOWA CITY VA MEDICAL CENTER
- **Principal Investigator:** Munir Tanas
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2016-10-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10881747

## Citation

> US National Institutes of Health, RePORTER application 10881747, Upstream regulation of TAZ and YAP in sarcomas: Towards combinatorial therapytargeting the Hippo pathway (5I01BX003644-07). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10881747. Licensed CC0.

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