A recent study published in Genes & Diseases has unveiled a novel mechanism by which the restriction of YWHAB-mediated YAP cytoplasmic retention plays a crucial role in maintaining stemness and chemoresistance in ovarian cancer peritoneal metastasis (OCPM). Researchers have found that the down-regulation of YWHAB in OCPM cells promotes the activation of YAP signaling, enhancing the cancer cells' ability to resist chemotherapy and maintain stem-like characteristics. This discovery may lead to innovative therapeutic strategies targeting the YWHAB-YAP pathway to combat the high mortality associated with ovarian cancer metastasis.

Ovarian cancer peritoneal metastasis is known for its aggressive nature and poor prognosis. Despite neoadjuvant chemotherapy (NACT), many patients relapse due to the survival of cancer stem cells within the peritoneal microenvironment. In this study, the researchers utilized tandem mass tag- and tissue microarray-based proteomic approaches to investigate molecular changes in residual tumor tissues after chemotherapy. They identified YWHAB as a critical regulator that, when restricted, leads to increased YAP nuclear accumulation and subsequent activation of YAP target genes, ultimately promoting tumor stemness and resistance.

The study demonstrated that YWHAB down-regulation not only correlates with poor chemotherapy response but also actively contributes to maintaining a stem cell-like phenotype in ovarian cancer cells. Experimental models showed that knocking down YWHAB significantly increased the diameter and number of tumor spheroids, a hallmark of enhanced stemness. Moreover, YWHAB knockdown cells exhibited heightened resistance to cisplatin, a common chemotherapeutic agent used in treating ovarian cancer.

Further mechanistic studies revealed that YWHAB directly interacts with YAP, facilitating its cytoplasmic retention and thereby inhibiting its nuclear activity. However, when YWHAB levels decrease, YAP translocates to the nucleus, where it binds to TEAD transcription factors and activates gene expression promoting cell proliferation, stemness, and drug resistance. In particular, the SH3 domain in YAP was found to be essential for binding with YWHAB, suggesting that disrupting this interaction may serve as a novel therapeutic approach.

In vivo experiments using mouse models further supported these findings, demonstrating that YWHAB deficiency significantly increased tumor formation and metastasis. The research team also identified epigenetic changes in the YWHAB promoter that could explain its down-regulation in resistant cancer cells.

This study not only provides insight into the molecular basis of chemoresistance in ovarian cancer but also suggests that therapies targeting the YWHAB-YAP interaction could potentially improve outcomes for patients suffering from OCPM. Further research is needed to explore targeted YAP inhibition as a viable strategy in clinical settings.

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Reference
Chang Liu, Lei Shi, Zijun Meng, Manlin Zhang, Zhiqi Zhang, Yunzhe Li, Kaiwen Du, Muyao Yang, Lin Qiu, Jing Feng, Yuchen He, Jiayun Liu, Hua Zhang, Hongbin Zhang, Tingyuan Lang, Zhuo Yang, Restriction of YWHAB-mediated YAP cytoplasmic retention is a novel mechanism underlying stemness maintenance and chemoresistance in ovarian cancer peritoneal metastasis, Genes & Diseases, 2025, 101519, https://doi.org/10.1016/j.gendis.2025.101519

Funding Information:
National Natural Science Foundation of China 82103056
Liaoning Province Science and Technology Plan Project (China) 2022JH2/101300045
Liaoning Province Science and Technology Plan Project (China) 2023-MS-060
Fundamental Research Funds for the Central Universities (China) LD202208
Liaoning Cancer Hospital and Institute, Dalian University of Technology "Medical Industrial Interdisciplinary Research Fund" LD2023028
Chongqing Science & Technology Commission of China CSTB2022NSCQ-MSX1413
Chongqing Science & Technology Commission of China CSTB2023TIAD-KPX0052
Shanghai Hongkou District Health Commission of China Hongwei 2101-01