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.

RNA-binding protein RBM28 can translocate from the nucleolus to the nucleoplasm to inhibit the transcriptional activity of p53.

RNA-binding protein RBM28 (RBM28), as a nucleolar component of spliceosomal small nuclear ribonucleoproteins, is involved in the nucleolar stress response. Whether and how RBM28 regulates tumor progression remains unclear. Here, we report that RBM28 is frequently overexpressed in various types of cancer and that its upregulation is associated with a poor prognosis. Functional and mechanistic assays revealed that RBM28 promotes the survival and growth of cancer cells by interacting with the DNA-binding domain of tumor suppressor p53 to inhibit p53 transcriptional activity. Upon treatment with chemotherapeutic drugs (e.g., adriamycin), RBM28 is translocated from the nucleolus to the nucleoplasm, which is likely mediated via phosphorylation of RBM28 at Ser122 by DNA checkpoint kinases 1 and 2 (Chk1/2), indicating that RBM28 may act as a nucleolar stress sensor in response to DNA damage stress. Our findings not only reveal RBM28 as a potential biomarker and therapeutic target for cancers but also provide mechanistic insights into how cancer cells convert stress signals into a cellular response linking the nucleolus to regulation of the tumor suppressor p53.