Abstract 5414: The RNA-binding protein HNRNPH1 regulates the expression of cell cycle-related genes to promote glioblastoma progression

Abstract Heterogeneous nuclear ribonucleoprotein H1 (HNRNPH1) is a critical regulator of several aspects of RNA metabolism, including RNA stability and splicing. Alteration of the expression of RNA-binding proteins, such as HNRNPH1, has been shown to affect the RNA life cycle. This, in turn, results in the production of abnormal proteins that may promote the development of cancer. While aberrant expression of HNRNPH1 has been linked to several neuronal-related disorders, its role in the progression of glioblastoma (GBM), the most frequent and aggressive primary brain tumor, is still poorly understood. Given our previous findings that HNRNPH1 binds the RNA of several genes involved in cell-cycle regulation and cell proliferation, we hypothesized that HNRNPH1 regulates cell division and glioblastoma growth. Analyses of GBM patient data from The Cancer Genome Atlas database, combined with tissue microarray immunostaining and qPCR analyses of patient-derived tumors and patient-derived glioblastoma cells (PDGCs), revealed that HNRNPH1 was upregulated in GBM compared to normal brain. Single-cell RNAseq data showed that HNRNPH1 was more expressed in malignant cells than in other cells within the tumor microenvironment, and its expression was associated with specific cellular states. Knocking out HNRNPH1 in both U87 cells and PDGCs using the CRISPR/Cas9 system caused the downregulation of several genes involved in cell division, such as AURKB, ESPL1, PRC1, and UBE2S. This was associated with an increased number of cells stuck in G2M, reduced cell proliferation, abnormal cell morphology, and an increase in polynucleated cells. Silencing HNRNPH1 in vivo suppressed the tumor growth of PDGC-originated intracranial xenografts and had significant survival benefits. Together, our results showed the critical importance of HNRNPH1 in cell cycle progression and tumor growth, with a potential impact on developing novel strategies to overcome the current limitations of GBM therapies. Citation Format: Genaro Villa, Paolo Alimonti, Joseph Toker, Raziye Piranlioglu, Andrew Chiocca, Alexa Lauinger, E. Antonio Chiocca, Marco Mineo. The RNA-binding protein HNRNPH1 regulates the expression of cell cycle-related genes to promote glioblastoma progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5414.