NPM1 histone chaperone is upregulated in glioblastoma to promote cell survival and maintain nucleolar shape

Abstract

Glioblastoma (grade IV glioma) is the most common and aggressive adult brain tumor. A better understanding of the biology of glioblastoma cells is crucial to identify molecular targets stimulating cell death. NPM1 (nucleophosmin) is a multifunctional chaperone that plays an important role in cancer development. Herein, NPM1 was analyzed by immunohistochemistry in human astrocytic gliomas. NPM1 was detected in all tumors but with a significantly higher staining intensity in grade IV than in low grade tumors. Depletion of NPM1 had only modest effects on the viability of U251MG, U1242MG, and U343MGa Cl2:6 glioma cells, despite alterations in nucleolar morphology. Glioma cell cultures depleted of NPM1 exposed to micromolar levels of actinomycin D were more prone to cell death (apoptosis) compared to cultures retaining NPM1. We had previously found that NPM1 binds to linker histone H1.5. Here we could show that silencing of H1.5 triggered glioma cell apoptosis as evidenced by a marked increase in both the numbers of cleaved caspase-3+ cells and in the amounts of cleaved PARP. Enforced expression of NPM1 suppressed apoptosis in H1.5 depleted glioma cells. Although our studies would suggest little effectiveness of targeting NPM1 alone there could be potential using it as a combination treatment.

Nuclear phosphatidylinositol 3,4,5-trisphosphate interactome uncovers an enrichment in nucleolar proteins

“…PARP1-dependent PARylation of histone H1 has been shown to remove this histone from the chromatin, hence causing it to relax (107). Nucleophosmin binds to histone H1.5 and has a silencing effect on this linker histone (105). A link between histone H1 and PPIn has previously been reported, demonstrating its interaction with PtdIns(4,5)P2 via its C-terminal region (57).…”

“…Altogether, these studies suggest that the organisation of proteins and lipids within the nucleolus is affected by the active transcription of rRNA. Interestingly, both PARP1 and nucleophosmin are also histone H1 interacting proteins (105), which is emerging to play important roles in the structure and integrity of the nucleolus (106). PARP1-dependent PARylation of histone H1 has been shown to remove this histone from the chromatin, hence causing it to relax (107).…”

Molecules that target nucleophosmin for cancer treatment: an update

“…NPM1 is over-expressed in a variety of solid tumours of different histological origin including prostate [47], liver [48], thyroid [49], colon [50], gastric [51], pancreas [52], glioma and glioblastoma [53, 54], astrocytoma [55] and others. NPM1 overexpression often correlates with mitotic index and metastatization and it has been proposed as an adverse prognostic marker in a number of such malignancies [5, 56].…”

Identification of replication-dependent and replication-independent linker histone complexes: Tpr specifically promotes replication-dependent linker histone stability

“…The group 1 proteins included two proteins that had previously been identified as histone chaperones, nucleolin and nucleophosmin (NPM1) [ 18 ]. Nucleolin and nucleophosmin are broad specificity histone binding proteins and have been found to associate with both core and linker histones [ 11 , 19 – 22 ]. Group 1 also included the SSRP subunit of the FACT complex, which also has been shown to interact with both core and linker histones [ 15 , 23 ].…”