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Proteasome stress activates YAP/TAZ through the RAP2-MAP4Ks-LATS1/2 pathway and its therapeutic implications in solid

Xin Wang1, Yuan Gu1,2, Zhenxing Zhong1

  • 1Institute of Pediatrics, Children's Hospital of Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, State Key Laboratory of Genetic Engineering, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China.

Proceedings of the National Academy of Sciences of the United States of America
|December 18, 2025
PubMed

Insights

Proteasome inhibitors are limited in solid tumors due to Hippo pathway activation. Blocking yes-associated protein (YAP)/TAZ overcomes this resistance, offering a new combination therapy strategy for aggressive cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • Proteasome inhibitors are effective in hematologic cancers but not solid tumors.
  • Drug resistance in cancers is often linked to activation of yes-associated protein (YAP)/TAZ, key effectors of the Hippo pathway.
  • The precise mechanisms underlying proteasome inhibitor resistance in solid tumors remain unclear.

Purpose of the Study:

  • To investigate the role of proteasome stress in activating the Hippo pathway in solid tumor cells.
  • To elucidate the signaling cascade linking proteasome inhibition to YAP/TAZ activation.
  • To evaluate the therapeutic potential of combining proteasome inhibitors with YAP/TAZ inhibition in solid tumors.

Main Methods:

  • Utilized proteasome inhibition in solid tumor cells to induce proteasome stress.
  • Investigated the ubiquitination and inactivation of RAP2 upon proteasome inhibition.
  • Analyzed the disruption of the RAP2-MAP4Ks-NF2-LATS1/2 signaling pathway.
  • Assessed the impact of YAP/TAZ activation on cell survival and drug resistance.
  • Evaluated the efficacy of combined proteasome and YAP/TAZ inhibition in diffuse-type gastric cancer models.

Main Results:

  • Proteasome stress was identified as an upstream signal activating the Hippo pathway in solid tumor cells.
  • Proteasome inhibition led to RAP2 ubiquitination and inactivation, disrupting the RAP2-MAP4Ks-NF2-LATS1/2 pathway.
  • This disruption resulted in the activation of YAP/TAZ, promoting cell survival and resistance to proteasome inhibitors.
  • Inhibition of YAP/TAZ restored cancer cell sensitivity to proteasome inhibitors.
  • Combined inhibition of proteasome and YAP/TAZ effectively suppressed tumor growth in diffuse-type gastric cancer.

Conclusions:

  • Proteasome stress is an upstream activator of the Hippo pathway in solid tumors.
  • YAP/TAZ activation mediates resistance to proteasome inhibitors in solid tumors.
  • Targeting YAP/TAZ in combination with proteasome inhibitors presents a promising therapeutic strategy for solid tumors, including diffuse-type gastric cancer.
Keywords:
Hippo pathwayYAPdrug repurposingproteasomesolid tumor

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