Downregulation of HINFP induces senescence-associated secretory phenotype to promote metastasis in a non-cell-autonomous manner in bladder cancer.

Transcription dysregulation is a salient characteristic of bladder cancer (BC), but no appropriate therapeutic target for it has been established. Here, we found that heterogeneous downregulation of histone H4 transcription factor (HINFP) was associated with senescence in BC tissues and that lower HINFP expression could predict an unfavorable outcome in BC patients. Knockout of HINFP transcriptionally inhibited H1F0 and H1FX to trigger DNA damage, consequently inducing cell senescence to repress the proliferation and growth of BC cells. However, the senescence-associated secretory phenotype, characterized by increases in MMP1/3, enhances the invasion and metastasis of non-senescent BC cells. Histone deacetylase inhibitors (HDACis) could efficiently eliminate the senescent cells induced by HINFP knockout to suppress the invasion and metastasis of BC cells. Our study suggests that HDACis, widely used in multiple cancer types in a clinical context, may also benefit BC patients with metastases induced by cell senescence.