Gastric cancer (GC) remains one of the leading causes of cancer-related mortality worldwide, with its aggressive metastatic behavior and limited therapeutic options contributing to poor patient outcomes. Although transcriptional dysregulation is known to drive tumor progression, the role of transcriptional cofactors in GC development remains elusive.

In a recent Genes & Diseases study, researchers from Anhui Medical University, the First Hospital of Jilin University, and Nantong First People's Hospital investigated the role of Hairy and Enhancer of Split 6 (Hes6), a transcriptional cofactor belonging to the HES family, and demonstrated its critical involvement in gastric carcinogenesis through the regulation of epithelial–mesenchymal transition (EMT) and PI3K/AKT signaling.

Hes6 is distinct among the HES family because it possesses a shortened basic helix-loop-helix domain that prevents direct DNA binding, necessitating its function as a transcriptional cofactor that modulates gene expression through interactions with other transcription factors.

Bioinformatic analysis of the TCGA and TNMplot databases, alongside validation in clinical samples, demonstrated that Hes6 is significantly up-regulated in gastric cancer tissues compared with adjacent normal tissues. Increased Hes6 expression was associated with an unfavorable prognosis in selected patient cohorts, suggesting its potential clinical relevance as a prognostic biomarker.

Functional characterization using in vitro assays in gastric cancer cell lines, including AGS, SGC 7901, and HGC 27, revealed that stable overexpression of Hes6 dramatically promotes cell proliferation, colony formation, migration, and invasion. Conversely, lentiviral-mediated suppression of Hes6 inhibited these malignant traits and increased the rate of cellular apoptosis. In vivo validation using BALB/c nude mouse xenograft models confirmed that Hes6 facilitates tumor formation and expansion, as evidenced by increased tumor weight, volume, and Ki-67 expression in groups overexpressing the gene.

Protein interaction studies, co-immunoprecipitation, molecular docking, and immunofluorescence assays confirmed that Hes6 interacts with Twist1 and promotes its stability by reducing its natural protein degradation rate. Given the established role of Twist1 in regulating EMT, this study further showed that Hes6 overexpression induces changes in key EMT markers, including decreased E-cadherin and increased N-cadherin, vimentin, and Snail expression. This stabilization of Twist1 by Hes6 facilitates EMT, thereby enhancing the metastatic potential of GC cells.

Furthermore, transcriptome sequencing and subsequent KEGG enrichment analysis identified the PI3K/AKT signaling pathway as a primary mediator of Hes6-driven oncogenesis. Hes6 expression levels were positively associated with the phosphorylation of PI3K (p-P85) and AKT (p-AKT). Pharmacological inhibition of this pathway using the PI3K inhibitor LY294002 significantly attenuated Hes6-induced malignant phenotypes, demonstrating that activation of this pathway is essential for Hes6-mediated oncogenic activity. These findings suggest that the Hes6–Twist1 complex and the associated PI3K/AKT signaling axis represent promising therapeutic targets for gastric cancer.

The authors acknowledge that the current study has limitations, including insufficient mechanistic depth, gaps in the overall research framework, and limited robustness of the experimental models. They emphasize the need for validation in additional in vivo models, investigation of potential off-target effects of Hes6 inhibition, and exploration of other signaling pathways to better establish Hes6 as a therapeutic target for gastric cancer.

In conclusion, this study establishes Hes6 as a key molecular regulator that enhances malignant phenotypes by interacting with Twist1 and activating oncogenic PI3K/AKT signaling pathways, highlighting its potential as a therapeutic target for gastric cancer.

Reference
Title of the original paper: Transcription cofactor Hes6 interacts with Twist1 to facilitate EMT and promote gastric carcinogenesis by activating the PI3K/AKT signaling
Journal : Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.
DOI: https://doi.org/10.1016/j.gendis.2025.101674

Funding Information:
Key Scientific Research Projects of Anhui Higher Education Institutions in 2023 (China) (No. 2023AH050573)
2023 Anhui Province Fuyang City Health Research Project (China) (No. FY2023-027)
Key Research and Development Project of the Anhui Provincial Department of Science and Technology (China) (No. 202004j07020036)
Key Teaching Research Project of the Anhui Provincial Department of Education (China) (No. 2020xsxxkc247)

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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.
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