title: KSHV induces aerobic glycolysis and angiogenesis through HIF-1-dependent upregulation of pyruvate kinase 2 in Kaposi's sarcoma.
abstract: Kaposi's sarcoma (KS) is a vascular neoplasm caused by infection of endothelial or endothelial precursor cells with the Kaposi's sarcoma-associated herpesvirus (KSHV/HHV8). Research efforts have focused on defining the molecular events explaining how KSHV promotes pathological angiogenesis and KS tumor formation. mTOR/HIF-1 is a fundamental pathway driving these processes through the upregulation of angiogenic and inflammatory proteins, including VEGF, ANGPTL4, and ANGPT2. Interestingly, HIF-1 has also been implicated in the upregulation of metabolic genes associated with aerobic glycolysis and the growth of solid tumors. However, whether HIF-1 plays a role in regulating cell metabolism in KS remains unexplored. Here, we show that the HIF-1 metabolic effector, pyruvate kinase 2 (PKM2), is upregulated upon KSHV infection of endothelial cells and is necessary to maintain aerobic glycolysis in infected cells. We further demonstrate that PKM2 regulates KS angiogenic phenotype by acting as a coactivator of HIF-1 and increasing the levels of HIF-1 angiogenic factors, including VEGF. Indeed, inhibition of PKM2 expression blocked endothelial cell migration and differentiation and the angiogenic potential of KSHV-infected cells. We also investigated whether PKM2 regulates the angiogenic dysregulation induced by the KSHV-encoded G protein-coupled receptor (vGPCR), a viral oncogene that promotes Kaposi's sarcomagenesis through the upregulation of HIF angiogenic factors. Interestingly, we found that PKM2 controls vGPCR-induced VEGF paracrine secretion and vGPCR oncogenesis. Our findings provide a molecular mechanism for how HIF-1 dysregulation fuels both angiogenesis and tumor metabolism in KS and support further investigations on therapeutic approaches targeting HIF-1 and PKM2 for KS treatment.
authors.affiliation: Department of Oncology and Diagnostic Sciences, School of Dentistry, University of Maryland, 650 W. Baltimore Street, 7th North, Rm 7263, Baltimore, MD, 21201, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Ma
authors.affiliation: Department of Oncology and Diagnostic Sciences, School of Dentistry, University of Maryland, 650 W. Baltimore Street, 7th North, Rm 7263, Baltimore, MD, 21201, USA.
authors.forename: Harsh
authors.initials: H
authors.lastname: Patel
authors.affiliation: Wilmer Eye Institute, Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore, MD, 21287, USA.
authors.forename: Savalan
authors.initials: S
authors.lastname: Babapoor-Farrokhran
authors.affiliation: Department of Oncology and Diagnostic Sciences, School of Dentistry, University of Maryland, 650 W. Baltimore Street, 7th North, Rm 7263, Baltimore, MD, 21201, USA.|Greenebaum Cancer Center, University of Maryland, Baltimore, MD, 21201, USA.
authors.forename: Renty
authors.initials: R
authors.lastname: Franklin
authors.affiliation: Vascular Program, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
authors.forename: Gregg L
authors.initials: GL
authors.lastname: Semenza
authors.affiliation: Wilmer Eye Institute, Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore, MD, 21287, USA.
authors.forename: Akrit
authors.initials: A
authors.lastname: Sodhi
authors.affiliation: Department of Oncology and Diagnostic Sciences, School of Dentistry, University of Maryland, 650 W. Baltimore Street, 7th North, Rm 7263, Baltimore, MD, 21201, USA. smontaner@umaryland.edu.|Department of Pathology, School of Medicine, University of Maryland, Baltimore, MD, 21201, USA. smontaner@umaryland.edu.|Greenebaum Cancer Center, University of Maryland, Baltimore, MD, 21201, USA. smontaner@umaryland.edu.
authors.forename: Silvia
authors.identifier: http://orcid.org/0000-0002-6354-5898
authors.initials: S
authors.lastname: Montaner
mesh_terms: D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006019:Glycolysis; D019288:Herpesvirus 8, Human / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000473:pathology; D011770:Pyruvate Kinase / Q000096:biosynthesis*; D012514:Sarcoma, Kaposi / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation
chemical_list: D051793:Hypoxia-Inducible Factor 1; D009363:Neoplasm Proteins; D011770:Pyruvate Kinase
keywords: Angiogenesis; Cell metabolism; HHV-8; Human herpesvirus-8; Hypoxia inducible factor-1; KSHV; Kaposi’s sarcoma; Kaposi’s sarcoma-associated herpesvirus; Pyruvate kinase 2; VEGF