Phytomedicine : international journal of phytotherapy and phytopharmacology · 2026
USP16 functions as a novel deubiquitinase of YAP and a therapeutic target of isorhamnetin in gastric cancer.
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Li Yehua, Ren Siying, Zhang Qin, Chen Huanhuan, Ji Xiang, Shi Jiale, Yang Jinbo, Sun Biqiang, Bai Fangrui, Huang Hai, Zhou Shen'ao
Аннотация
BACKGROUND: Gastric cancer remains a major global health burden, and the development of effective therapeutic strategies targeting oncogenic signaling pathways remains an unmet clinical need. Yes-associated protein (YAP), a key effector of the Hippo pathway, is frequently activated in gastric cancer; however, the mechanisms controlling YAP protein stability beyond phosphorylation remain incompletely understood. Deubiquitinating enzymes (DUBs) represent important regulators of protein stability and may provide promising therapeutic targets.
PURPOSE: This study aimed to identify novel DUBs regulating YAP stability and elucidate the molecular mechanism underlying the anti-gastric cancer activity of the natural flavonoid isorhamnetin (ISO).
METHODS: YAP-interacting proteins were identified by affinity purification coupled with mass spectrometry. The molecular mechanisms of USP16-mediated YAP regulation were investigated using biochemical assays, ubiquitination and deubiquitination analyses, transcriptomic profiling, and in vitro and in vivo gastric cancer models. The interaction between ISO and USP16 was evaluated by molecular docking and microscale thermophoresis.
RESULTS: We identified USP16 as a previously unrecognized deubiquitinase of YAP. USP16 directly interacted with YAP and removed K48-linked polyubiquitin chains from YAP, primarily at Lys90 and Lys252, thereby preventing proteasomal degradation and enhancing YAP stability. Functionally, USP16 promoted gastric cancer cell proliferation, migration, tumor growth, and metastasis through YAP stabilization. Mechanistically, YAP transcriptionally activated USP16 expression through TEAD-dependent promoter regulation, establishing a positive feedback loop that sustained Hippo/YAP pathway activation. Furthermore, ISO was identified as a direct USP16-binding compound. ISO disrupted the USP16-YAP interaction, impaired USP16-mediated YAP deubiquitination, increased YAP ubiquitination and degradation, and suppressed gastric cancer progression in vitro and in vivo.
CONCLUSIONS: This study reveals a previously unidentified USP16-YAP regulatory axis that drives gastric cancer progression and demonstrates USP16 as a therapeutic target of ISO. These findings provide a mechanistic basis for the development of ISO-derived strategies targeting YAP stabilization in gastric cancer.
PURPOSE: This study aimed to identify novel DUBs regulating YAP stability and elucidate the molecular mechanism underlying the anti-gastric cancer activity of the natural flavonoid isorhamnetin (ISO).
METHODS: YAP-interacting proteins were identified by affinity purification coupled with mass spectrometry. The molecular mechanisms of USP16-mediated YAP regulation were investigated using biochemical assays, ubiquitination and deubiquitination analyses, transcriptomic profiling, and in vitro and in vivo gastric cancer models. The interaction between ISO and USP16 was evaluated by molecular docking and microscale thermophoresis.
RESULTS: We identified USP16 as a previously unrecognized deubiquitinase of YAP. USP16 directly interacted with YAP and removed K48-linked polyubiquitin chains from YAP, primarily at Lys90 and Lys252, thereby preventing proteasomal degradation and enhancing YAP stability. Functionally, USP16 promoted gastric cancer cell proliferation, migration, tumor growth, and metastasis through YAP stabilization. Mechanistically, YAP transcriptionally activated USP16 expression through TEAD-dependent promoter regulation, establishing a positive feedback loop that sustained Hippo/YAP pathway activation. Furthermore, ISO was identified as a direct USP16-binding compound. ISO disrupted the USP16-YAP interaction, impaired USP16-mediated YAP deubiquitination, increased YAP ubiquitination and degradation, and suppressed gastric cancer progression in vitro and in vivo.
CONCLUSIONS: This study reveals a previously unidentified USP16-YAP regulatory axis that drives gastric cancer progression and demonstrates USP16 as a therapeutic target of ISO. These findings provide a mechanistic basis for the development of ISO-derived strategies targeting YAP stabilization in gastric cancer.