Reactivating Hippo by drug compounds to suppress gastric cancer and enhance chemotherapy sensitivity

Sep 21, 2026

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Hippo signaling regulates organ size, tissue homeostasis, and tumorigenesis, and its loss with hyperactive YAP signaling is commonly seen in cancers. The study identifies a STRN3-containing PP2A phosphatase axis in gastric cancer and tests pharmacological reactivation of Hippo activity. It shows disulﬁram (DSF) blocks STRN3–PP2A binding and CX-6258 disrupts STRN3–MST1/2 interaction, reactivating Hippo via MST1/2 kinase dependence. The compounds inhibit DNA repair and sensitize gastric cancer to chemotherapy, while thiram analogs and copper ions further enhance effects.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages15

Reading Time38 min

AccessFree to download

Background

Hippo-YAP pathway and cancer relevance

Therapeutic strategy

Targeting the PP2A–STRN3–MST1/2 axis

Drug compounds and mechanisms

DSF and CX-6258 effects

MST1/2-dependent reactivation and DNA repair inhibition

Related analogs and potentiation

Thiram and copper ion enhancement

Overall conclusions

Pharmacological Hippo signal recovery for tumor treatment

RESEARCH ARTICLE Reactivating Hippo by drug compounds to suppress gastric cancer and enhance chemotherapy sensitivity Received for publication, January 10, 2024, and in revised form, April 12, 2024 Published, Papers in Press, April 22, 2024, [https://doi.org/10.1016/j.jbc.2024.107311](https://doi.org/10.1016/j.jbc.2024.107311) Zhifa Cao 1,2,‡, Yu Hou 1,‡, Zhangting Zhao2, Hui Zhang 1, Luyang Tian 1, Yiming Zhang2, Chao Dong3, Fenghua Guo4, Lijie Tan5, Yi Han2, Wenjia Wang 1, Shi Jiao 1, Yang Tang2, *, Liwei An2, *, and Zhaocai Zhou 1,6, * From the 1State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, China; 2Department of Stomatology, Department of Medical Ultrasound, Shanghai Tenth People’s Hospital, Tongji University Cancer Center, School of Medicine, Tongji University, Shanghai, China; 3Department of Medical Oncology, The First Afﬁliated Hospital of Kunming Medical University, Kunming, China; 4Department of General Surgery, Hua’shan Hospital, Fudan University Shanghai Medical College, Shanghai, China; 5Department of Thoracic Surgery, Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China; 6Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, China Reviewed by members of the JBC Editorial Board. Edited by Paul Shapiro The Hippo signaling pathway plays an essential role in organ size control and tumorigenesis. Loss of Hippo signal and hyperactivation of the downstream oncogenic YAP signaling are commonly observed in various types of cancers. We previously identiﬁed STRN3-containing PP2A phosphatase as a negative regulator of MST1/2 kinases (i.e., Hippo) in gastric cancer (GC), opening the possibility of selectively targeting the PP2Aa–STRN3–MST1/2 axis to recover Hippo signaling against cancer. Here, we further discovered 1) disulﬁram (DSF), an FDA-approved drug, which can similarly block the binding of STRN3 to PP2A core enzyme and 2) CX-6258 (CX), a chemical inhibitor, that can disrupt the interaction between STRN3 and MST1/2, both allowing reactivation of Hippo activity to inhibit GC. More importantly, we found these two compounds, via an MST1/2 kinase-dependent manner, inhibit DNA repair to sensitize GC towards chemotherapy. In addition, we identiﬁed thiram, a structural analog of DSF, can function similarly to inhibit cancer cell proliferation or enhance chemotherapy sensitivity. Interestingly, inclusion of copper ion enhanced such effects of DSF and thiram on GC treatment. Overall, this work demonstrated that pharmacological targeting of the PP2Aa–STRN3–MST1/2 axis by drug compounds can potently recover Hippo signal for tumor treatment. The evolutionarily conserved Hippo signaling pathway plays important roles in organ size control, tissue homeostasis, and tumorigenesis (1–3). In the canonical signaling cascade of mammalian Hippo pathway, MST1/2 kinases (i.e., Hippo) phosphorylate and activate LATS1/2 kinases, which in turn phosphorylate the transcriptional coactivators YAP/TAZ, causing their cytoplasmic sequestration and degradation. Once the Hippo signal is absent, YAP/TAZ will translocate into the ‡ These authors contributed equally to this work. * For correspondence: Zhaocai Zhou, [zhouzhaocai@fudan.edu.cn](zhouzhaocai@fudan.edu.cn); Liwei An, [lwan@tongji.edu.cn](lwan@tongji.edu.cn); Yang Tang, [tangyang@tongji.edu.cn](tangyang@tongji.edu.cn). nucleus, where they form a complex with TEAD family of transcription factors to promote the expression of downstream target genes such as CTGF and CYR61, leading to increased cell proliferation and decreased apoptosis (4–6). Accordingly, dysregulation of the Hippo-YAP signaling, for example, loss of Hippo signal and hyperactivation of YAP/TAZ are frequently observed in various types of tumors (7–9), making this pathway as an attractive drug target for cancer treatment. Growing efforts have been made to

FAQs

What is the main therapeutic target investigated in gastric cancer in this article?

The article targets the PP2A–STRN3–MST1/2 axis to selectively reactivate Hippo signaling against gastric cancer.

How do DSF and CX-6258 contribute to Hippo pathway reactivation?

DSF blocks the binding of STRN3 to the PP2A core enzyme, while CX-6258 disrupts the interaction between STRN3 and MST1/2, allowing MST1/2-dependent Hippo reactivation.

What is the proposed reason these compounds enhance chemotherapy sensitivity?

They inhibit DNA repair in a manner dependent on MST1/2 kinase activity, thereby sensitizing gastric cancer to chemotherapy.

Sep 21, 2026

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