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 KLF4K409Q mutated tumors harbor an upregulation of hypoxia dependent pathways. Detailed in vitro investigation further showed that the KLF4K409Q mutation induces HIF-1α through the reduction of prolyl hydroxylase activity and causes an upregulation of downstream HIF-1α targets. Finally, we demonstrate that KLF4K409Q 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.
Subject(s)
Gene Expression Regulation, Neoplastic/genetics , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Kruppel-Like Transcription Factors/genetics , Meningeal Neoplasms/genetics , Meningioma/genetics , Tumor Hypoxia/genetics , Animals , Cell Line, Tumor , Cell Proliferation , Gene Expression Regulation, Neoplastic/drug effects , Humans , Hypoxia/genetics , Hypoxia/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/drug effects , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Kruppel-Like Factor 4 , Kruppel-Like Transcription Factors/drug effects , Mechanistic Target of Rapamycin Complex 1/antagonists & inhibitors , Meningeal Neoplasms/metabolism , Meningioma/metabolism , Mice , Mice, Nude , Mutation , Neoplasm Transplantation , Prolyl Hydroxylases , Protein Kinase Inhibitors/pharmacology , RNA-Seq , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction , Sirolimus/analogs & derivatives , Sirolimus/pharmacology , Skull Base Neoplasms , Up-RegulationABSTRACT
Lung cancer is the leading cause of cancer-related death worldwide, in large part due to its high propensity to metastasize and to develop therapy resistance. Adaptive responses to hypoxia and epithelial-mesenchymal transition (EMT) are linked to tumor metastasis and drug resistance, but little is known about how oxygen sensing and EMT intersect to control these hallmarks of cancer. Here, we show that the oxygen sensor PHD3 links hypoxic signaling and EMT regulation in the lung tumor microenvironment. PHD3 was repressed by signals that induce EMT and acted as a negative regulator of EMT, metastasis, and therapeutic resistance. PHD3 depletion in tumors, which can be caused by the EMT inducer TGFß or by promoter methylation, enhanced EMT and spontaneous metastasis via HIF-dependent upregulation of the EGFR ligand TGFα. In turn, TGFα stimulated EGFR, which potentiated SMAD signaling, reinforcing EMT and metastasis. In clinical specimens of lung cancer, reduced PHD3 expression was linked to poor prognosis and to therapeutic resistance against EGFR inhibitors such as erlotinib. Reexpression of PHD3 in lung cancer cells suppressed EMT and metastasis and restored sensitivity to erlotinib. Taken together, our results establish a key function for PHD3 in metastasis and drug resistance and suggest opportunities to improve patient treatment by interfering with the feedforward signaling mechanisms activated by PHD3 silencing.Significance: This study links the oxygen sensor PHD3 to metastasis and drug resistance in cancer, with implications for therapeutic improvement by targeting this system. Cancer Res; 78(7); 1805-19. ©2018 AACR.
Subject(s)
Antineoplastic Agents/therapeutic use , Epithelial-Mesenchymal Transition/genetics , Erlotinib Hydrochloride/therapeutic use , Hypoxia-Inducible Factor-Proline Dioxygenases/metabolism , Lung Neoplasms/pathology , Protein Kinase Inhibitors/therapeutic use , Transforming Growth Factor alpha/metabolism , A549 Cells , Animals , Apoptosis Regulatory Proteins , Cell Hypoxia/genetics , Cell Line, Tumor , Drug Resistance, Neoplasm/genetics , ErbB Receptors/antagonists & inhibitors , Female , HCT116 Cells , Humans , Hypoxia-Inducible Factor-Proline Dioxygenases/genetics , Intracellular Signaling Peptides and Proteins/metabolism , Lung Neoplasms/genetics , Mice , Mice, Nude , Mitochondrial Proteins/metabolism , Neoplasm Metastasis/genetics , Tumor Microenvironment/physiology , Xenograft Model Antitumor AssaysABSTRACT
Cbx4 is a polycomb group protein that is also a SUMO E3 ligase, but its potential roles in tumorigenesis remain to be explored. Here, we report that Cbx4, but not other members of the Cbx family, enhances hypoxia-induced vascular endothelial growth factor (VEGF) expression and angiogenesis in hepatocellular carcinoma (HCC) cells through enhancing HIF-1α sumoylations at K391 and K477 in its two SUMO-interacting motifs-dependent mechanisms and increasing transcriptional activity of HIF-1. The Cbx4 expression is significantly correlated with VEGF expression, angiogenesis, and the overall survival of HCC patients and also in subcutaneously and orthotopically transplanted mice HCC models. Collectively, our findings demonstrate that Cbx4 plays a critical role in tumor angiogenesis by governing HIF-1α protein.
