(Press-News.org) 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.
# # # # #
Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.
Scopus CiteScore: 8.4
Impact Factor: 9.4
# # # # # #
More information: https://www.keaipublishing.com/en/journals/genes-and-diseases/
Editorial Board: https://www.keaipublishing.com/en/journals/genes-and-diseases/editorial-board/
All issues and articles in press are available online in ScienceDirect (https://www.sciencedirect.com/journal/genes-and-diseases ).
Submissions to Genes & Disease may be made using Editorial Manager (https://www.editorialmanager.com/gendis/default.aspx ).
Print ISSN: 2352-4820
eISSN: 2352-3042
CN: 50-1221/R
Contact Us: editor@genesndiseases.com
X (formerly Twitter): @GenesNDiseases (https://x.com/GenesNDiseases )
# # # # # #
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
END
A recent study published in Genes & Diseases reveals new insights into the relationship between immune cell characteristics, blood metabolites, and the risk of urolithiasis. Using Mendelian randomization (MR) and mediation analysis, the research highlights how genetically predicted blood metabolites mediate the association between specific immune cell profiles and the development of urinary stones. The findings shed light on potential pathogenic mechanisms and suggest novel therapeutic targets for this widespread and recurrent condition.
Urolithiasis, ...
A groundbreaking study published in Genes & Diseases has revealed that exogenous pyruvate significantly alleviates the symptoms of ulcerative colitis (UC) by targeting cytosolic phospholipase A2 (cPLA2). This discovery opens new avenues for the treatment of UC, which remains a chronic inflammatory bowel disease with limited therapeutic options. The study shows that pyruvate can suppress the TNFα/NFκB signaling pathway, which is pivotal in driving inflammation, thereby offering a novel approach to mitigating UC symptoms.
Ulcerative colitis is characterized by chronic intestinal inflammation, leading ...
A recent study published in Genes & Diseases explores the clinical implications of loss-of-function mutations in IKBKG/NEMO, a key regulator in the NF-κB signaling pathway. These mutations are linked to a range of rare and often severe genetic disorders, including Incontinentia Pigmenti (IP), Anhidrotic Ectodermal Dysplasia with Immunodeficiency (EDA-ID), Immunodeficiency (ID), and NEMO Deleted Exon 5 Autoinflammatory Syndrome (NDAS). The research aims to provide a comprehensive review of the diverse clinical manifestations ...
Images
A new blue fluorescent molecule set new top emission efficiencies in both solid and liquid states, according to a University of Michigan-led study that could pave the way for applications in technology and medicine.
Able to absorb light and emit it at lower energy levels, fluorescent molecules called fluorophores glow in OLED displays and help doctors and scientists figure out what's happening in cells and tissues. They need to be solid in displays and many sensing applications, but liquids are typically preferred for biological uses. ...
For a decade, scientists have believed that plants sensed temperature mainly through specialized proteins, and mainly at night when the air is cool. New research suggests that during the day, another signal takes over. Sugar, produced in sunlight, helps plants detect heat and decide when to grow.
The study, led by Meng Chen, a University of California, Riverside professor of cell biology, shows that plants rely on multiple heat-sensing systems, and that sugar plays a central and previously unrecognized role in daytime temperature response. The findings, published in Nature Communications, reshape a long-standing view of how plants ...
The lucrative pay for American CEOs often makes headlines. In 1965, CEO compensation was 22 times higher than the pay of an average worker. In recent years, CEOs have been paid 344 times more than the people who work for them.
The personality of a CEO is one factor driving the increase in executive compensation, according to a new study from a team of researchers that includes Sam M. Walton College of Business strategic management professor Jason Ridge.
Leaders with a Machiavellian personality, someone who is self-interested, unemotional and manipulative, earn more than $1.5 million a year in additional pay. While ...
While the current generation of artificial intelligence chatbots still flub basic facts, the systems answer with such confidence that they’re often more persuasive than humans.
Adults, even those such as lawyers with deep domain knowledge, still regularly fall for this. But spotting errors in text is especially difficult for children, since they often don’t have the contextual knowledge to sniff out falsehoods.
University of Washington researchers developed the game AI Puzzlers to show kids an area where AI systems still typically and blatantly ...
By Greg Watry, UC Davis
Archaeologists have long thought that monumental architecture — large, human-built structures that emphasize visibility — were products of societies with power structures, including social hierarchy, inequality and controlled labor forces. But this notion is being questioned as researchers uncover evidence that hunter-gatherer groups also built such structures.
In new research published June 24 in the journal Antiquity, University of California researchers report evidence of monumental structures built by hunter-gatherer groups at Kaillachuro, a collection of burial mounds located in the Titicaca Basin of the ...
The strength of certain neural connections can predict how well someone can learn math, and mild electrically stimulating these networks can boost learning, according to a study published on July 1st in the open-access journal PLOS Biology by Roi Cohen Kadosh from University of Surrey, United Kingdom, and colleagues.
When it comes to cognitive skills like reading and math, early advantages tend to compound over time. Mathematical abilities, however, seem to plateau from childhood to adulthood, raising the possibility that innate brain characteristics ...
Putting the brakes on an enzyme might rescue neurons that are dying due to a type of Parkinson’s disease that’s caused by a single genetic mutation, according to a new Stanford Medicine-led study conducted in mice.
The genetic mutation causes an enzyme called leucine-rich repeat kinase 2, or LRRK2, to be overactive. Too much LRRK2 enzyme activity changes the structure of brain cells in a way that disrupts crucial communication between neurons that make the neurotransmitter dopamine and cells in the striatum, ...