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Druggable linker histone variant H1-10 promotes ribosome biogenesis and nucleolar assembly in prostate cancer

ABSTRACT: Linker histone H1 stabilizes chromatin, but the functions of its variants remain incompletely understood. Among the seven somatic H1 variants, H1-10 has the minimal sequence similarity to others, suggesting a distinct biological role. Here, we show that H1-10, unlike other somatic variants, localizes predominantly to the nucleolus, where it promotes nucleolar assembly through liquid-liquid phase condensation and enhances RNA polymerase I occupancy at ribosomal DNA (rDNA). This results in amplified rRNA transcription and increased global protein synthesis. H1-10 is upregulated across multiple cancer types and, in prostate cancer, selectively augments E2F3 translation, thereby activating a broad cell-growth transcriptional program. Through structure-based screening, we identified first-in-class small-molecule inhibitors that disrupt H1-10 DNA binding and nucleolar localization, effectively suppressing prostate tumor growth without overt toxicity. Lead optimization produced compound CN27 (IC₅₀ = 180 nM; >100-fold selectivity of H1-10 over H1-1/H1-6), which demonstrated potent efficacy in castration-resistant prostate cancer models. Collectively, our findings uncover a critical role of H1-10 in ribosome biogenesis and oncogenic translation, providing proof-of-concept for pharmacological targeting of histone variants.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

DISEASE(S): Prostate Adenocarcinoma

SUBMITTER: Wenzheng Wang

LAB HEAD: Haiyang Guo

PROVIDER: PXD078382 | Pride | 2026-05-18

REPOSITORIES: Pride

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Druggable linker histone variant H1-10 promotes ribosome biogenesis and nucleolar assembly in prostate cancer

Project description:Linker histone H1 stabilizes chromatin, but the functions of its variants remain incompletely understood. Among the seven somatic H1 variants, H1-10 has the minimal sequence similarity to others, suggesting a distinct biological role. Here, we show that H1-10, unlike other somatic variants, localizes predominantly to the nucleolus, where it promotes nucleolar assembly through liquid-liquid phase condensation and enhances RNA polymerase I occupancy at ribosomal DNA (rDNA). This results in amplified rRNA transcription and increased global protein synthesis. H1-10 is upregulated across multiple cancer types and, in prostate cancer, selectively augments E2F3 translation, thereby activating a broad cell-growth transcriptional program. Through structure-based screening, we identified first-in-class small-molecule inhibitors that disrupt H1-10 DNA binding and nucleolar localization, effectively suppressing prostate tumor growth without overt toxicity. Lead optimization produced compound CN27 (IC₅₀ = 180 nM; >100-fold selectivity of H1-10 over H1-1/H1-6), which demonstrated potent efficacy in castration-resistant prostate cancer models. Collectively, our findings uncover a critical role of H1-10 in ribosome biogenesis and oncogenic translation, providing proof-of-concept for pharmacological targeting of histone variants.

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Project description: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.

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