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 leukaemia, 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, tumour stage & lymph node metastasis, and with high levels of cell-cycle-related proteins.

At the same time, its knockdown decreased xenograft tumour 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 signalling, cell cycle, autophagy, TNF signalling, 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 signalling 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 tumours via inhibiting the menin/TFAP2C/β-catenin signalling 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 signalling, suggesting its potential as a therapeutic target and prognostic marker in BLCA.

Source: Compuscript Ltd