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KLF4 K409Q –mutated meningiomas show enhanced hypoxia signaling and respond to mTORC1 inhibitor treatment
- Source :
- Acta Neuropathologica Communications, Vol 8, Iss 1, Pp 1-11 (2020), Acta Neuropathologica Communications 8(1), 41 (2020). doi:10.1186/s40478-020-00912-x, Acta Neuropathologica Communications
- Publication Year :
- 2020
- Publisher :
- BMC, 2020.
-
Abstract
- Meningioma represents the most common primary brain tumor in adults. Recently several non-NF2 mutations in meningioma have been identified and correlated with certain pathological subtypes, locations and clinical observations. Alterations of cellular pathways due to these mutations, however, have largely remained elusive. Here we report that the Krueppel like factor 4 (KLF4)-K409Q mutation in skull base meningiomas triggers a distinct tumor phenotype. Transcriptomic analysis of 17 meningioma samples revealed that KLF4 K409Q mutated tumors harbor an upregulation of hypoxia dependent pathways. Detailed in vitro investigation further showed that the KLF4 K409Q mutation induces HIF-1α through the reduction of prolyl hydroxylase activity and causes an upregulation of downstream HIF-1α targets. Finally, we demonstrate that KLF4 K409Q mutated tumors are susceptible to mTOR inhibition by Temsirolimus. Taken together, our data link the KLF4K409Q mediated upregulation of HIF pathways to the clinical and biological characteristics of these skull base meningiomas possibly opening new therapeutic avenues for this distinct meningioma subtype.
- Subjects :
- pharmacology [Protein Kinase Inhibitors]
drug effects [Gene Expression Regulation, Neoplastic]
analogs & derivatives [Sirolimus]
genetics [Gene Expression Regulation, Neoplastic]
lcsh:RC346-429
drug effects [Kruppel-Like Transcription Factors]
Mice
Meningeal Neoplasms
Edema
RNA-Seq
Hypoxia
antagonists & inhibitors [Mechanistic Target of Rapamycin Complex 1]
genetics [Meningeal Neoplasms]
Reverse Transcriptase Polymerase Chain Reaction
genetics [Meningioma]
KLF4
genetics [Tumor Hypoxia]
Up-Regulation
Gene Expression Regulation, Neoplastic
K409Q
Meningioma
Signal Transduction
Kruppel-Like Transcription Factors
pharmacology [Sirolimus]
Mice, Nude
Mechanistic Target of Rapamycin Complex 1
genetics [Hypoxia]
Skull Base Neoplasms
Prolyl Hydroxylases
Kruppel-Like Factor 4
metabolism [Meningeal Neoplasms]
Cell Line, Tumor
genetics [Hypoxia-Inducible Factor 1, alpha Subunit]
otorhinolaryngologic diseases
Animals
Humans
HIF
ddc:610
neoplasms
Protein Kinase Inhibitors
lcsh:Neurology. Diseases of the nervous system
Cell Proliferation
Sirolimus
Research
metabolism [Hypoxia-Inducible Factor 1, alpha Subunit]
genetics [Kruppel-Like Transcription Factors]
Hypoxia-Inducible Factor 1, alpha Subunit
metabolism [Hypoxia]
nervous system diseases
metabolism [Meningioma]
Mutation
Tumor Hypoxia
drug effects [Hypoxia-Inducible Factor 1, alpha Subunit]
Neoplasm Transplantation
Subjects
Details
- Language :
- English
- ISSN :
- 20515960
- Volume :
- 8
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Acta Neuropathologica Communications
- Accession number :
- edsair.pmid.dedup....306ca425261f423e431772a1a39f2e78