Small molecules targeting histone variant H1-10

While the linker histone H1 is recognized for its role in stabilizing higher-order chromatin structures, the distinct functions of its variants remain underexplored. In this study, we uncover that the H1-10 is markedly overexpressed in prostate cancer and associates with a poor prognosis. H1-10 is mainly localized to the nucleolus, where it facilitates nucleolar assembly through liquid condensation. H1-10 amplifies ribosomal RNA (rRNA) transcription by directly associating with RNA polymerase I (Pol I), thereby enhancing Pol I binding affinity for ribosomal DNA (rDNA). This results in expanded production of rRNA and elevated global protein translation. By further investigation, we found that H1-10 boosts the protein translation of transcription factor E2F3, which in turn induces the transcription of cell growth genes by increasing the level of CTD serine 5 phosphorylated RNA polymerase II at gene promoters. Critically, through high-throughput virtual screening, we identified specific small molecules that inhibit H1-10 by targeting its DNA binding domain. On-target validations showed these molecules blocked H1-10-mediated Pol I rDNA occupancy, global protein translation and prostate tumor growth in vitro and in vivo. In summary, our study reveals the critical role of H1-10 in ribosome biogenesis and prostate cancer progression, and pioneers the pharmacological targeting of an H1 variant, highlighting the therapeutic promise of targeting histone variants.