HNRNPH1 drives glioblastoma progression by regulating the splicing of cell cycle genes

Abstract

Although glioblastoma (GBM) harbors multiple genetic abnormalities leading to cell cycle deregulation, a functional mitotic checkpoint is essential to prevent mitotic catastrophe and tumor cell death. Here, we identify the RNA-binding protein HNRNPH1 as a key post-transcriptional modulator of G2/M checkpoint-associated genes in GBM. HNRNPH1 is overexpressed in malignant cells, especially in the neural- and oligodendrocyte-progenitor-like state, and its expression levels are higher in non-hypoxic regions of the tumor. Knocking out HNRNPH1 causes aberrant splicing and downregulation of several genes involved in cell division. These molecular alterations are associated with G2/M cell cycle arrest, reduced cell proliferation, abnormal cell morphology, and increased nuclear fragmentation. Silencing HNRNPH1 in vivo inhibits the tumor growth of patient-derived GBM cell-originated intracranial xenografts and has significant survival benefits. Together, our results show the critical importance of HNRNPH1 in cell cycle progression and tumor growth, potentially impacting the development of novel strategies to treat GBM.