DNA methylation-mediated silencing of HNF1B promotes bladder cancer progression

Hepatocyte nuclear factor 1 homeobox B (HNF1B), a developmentally crucial transcription factor, demonstrates tumor-suppressive functions in several cancers, with epigenetic silencing being a known mechanism, as seen in malignancies like ovarian and prostate carcinoma. Its functional significance in bladder cancer pathogenesis is far less clear.

Our analysis of clinical cohorts identified low HNF1B expression as an independent prognostic factor that is significantly associated with adverse clinicopathological characteristics and poorer survival in bladder cancer patients. Functionally, knockdown of HNF1B promoted bladder cancer cell proliferation, migration, and invasion, whereas its overexpression suppressed these malignant phenotypes in vitro and attenuated tumor growth in vivo. Mechanistically, HNF1B silencing was primarily mediated by promoter hypermethylation. Furthermore, we demonstrated that HNF1B exerts its tumor-suppressive roles by concurrently inhibiting the mitogen-activated protein kinase (MAPK) signaling pathway and the epithelial-mesenchymal transition (EMT) process.

Our study unveils a novel epigenetic mechanism in bladder cancer, whereby promoter hypermethylation silences HNF1B, thereby promoting tumor progression through activation of the MAPK pathway. These findings establishe HNF1B status as a potential biomarker for stratifying patients who may benefit from targeted therapies against this pathway.