Bladder cancer (BLCA) is one of the most prevalent malignancies of the urinary system, prone to recurrence, metastasis, and drug resistance. Its complex biological characteristics underscore the need to explore the molecular mechanisms underlying various aspects of BLCA tumorigenesis, while concurrently identifying novel therapeutic targets.
Menin, encoded by the MEN1 gene, has been implicated in the initiation and progression of various cancers, including leukemia, breast, prostate, and liver cancers; however, its role in the progression of BLCA remains elusive.
A recent study published in the Genes & Diseases journal, conducted by researchers from Harbin Medical University, Chongqing Three Gorges Medical College, Shanghai Jiaotong University School of Medicine, and Université Claude Bernard Lyon 1, investigated the role of menin and its associated mechanisms in the progression of bladder cancer.
Initial mRNA and protein expression analysis of human BCLA tissues revealed that higher MEN1 levels were associated with poor overall survival, correlated positively with patients' age, tumor stage & lymph node metastasis, and with high levels of cell-cycle-related proteins. At the same time, its knockdown decreased xenograft tumor size in a nude mouse model, which establishes its oncogenic role in BLCA.
MEN1 knockdown inhibited BLCA proliferation and induced G1/S phase cell cycle arrest, suggesting that menin promotes proliferation by enhancing cell cycle transition in these cells. Consequently, RNA sequencing and KEGG analysis revealed the enrichment of differentially expressed genes in pathways including the Wnt signaling, cell cycle, autophagy, TNF signaling, mitophagy, polycomb repressive complex, nucleotide excision repair, DNA replication, and apoptosis, among others. Additionally, MEN1-KD downregulates β-catenin at both the mRNA and protein levels. Mechanistically, menin regulates CTNNB1 transcription by binding to its proximal promoter, thus activating the Wnt/β-catenin signaling pathway in BLCA cells.
The authors further showed that menin upregulates TFAP2C expression by binding to its proximal promoter, mediated by the MLL complex, in BLCA cells, which suggests that TFAP2C is a new downstream target for menin in BLCA cells. Experiments involving TFAP2C and CTNNB1 knockdown unravelled that TFAP2C regulates CTNNB1 gene transcription by binding to its proximal promoter, and that TFAP2C is essential for menin-mediated CTNNB1 transcription in BLCA cells.
Furthermore, BAY-15522, a small molecule inhibitor of menin, was shown to suppress the proliferation and growth of BLCA tumors via inhibiting the menin/TFAP2C/β-catenin signaling axis, which further validates the tumorigenic role of menin in BLCA progression.
In conclusion, this study demonstrated that menin promotes BLCA malignancy by enhancing TFAP2C/β-catenin signaling, suggesting its potential as a therapeutic target and prognostic marker in BLCA.
Reference
Title of the original paper: Menin facilitates the cell proliferation of bladder cancer via modulating the TFAP2C/β-catenin axis
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.2025.101565
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