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A system-level approach identifies HIF-2α as a critical regulator of chondrosarcoma progression

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Title
A system-level approach identifies HIF-2α as a critical regulator of chondrosarcoma progression
Author(s)
Hyeonkyeong Kim; Yongsik Cho; Hyeon-Seop Kim; Donghyun Kang; Donghyeon Cheon; Yi-Jun Kim; Moon Jong Chang; Kyoung Min Lee; Chong Bum Chang; Seung-Baik Kang; Hyun Guy Kang; Jin-Hong Kim
Subject
HYPOXIA-INDUCIBLE FACTORS, ; SET ENRICHMENT ANALYSIS, ; MATRIX METALLOPROTEINASES, ; CANCER, ; BONE, ; INHIBITION, ; EXPRESSION, ; MUTATIONS, ; CARTILAGE, ; PATHWAYS
Publication Date
2020-10
Journal
NATURE COMMUNICATIONS, v.11, no.1, pp.5023
Publisher
NATURE PUBLISHING GROUP
Abstract
© 2020, The Author(s). Chondrosarcomas, malignant cartilaginous neoplasms, are capable of transitioning to highly aggressive, metastatic, and treatment-refractory states, resulting in significant patient mortality. Here, we aim to uncover the transcriptional program directing such tumor progression in chondrosarcomas. We conduct weighted correlation network analysis to extract a characteristic gene module underlying chondrosarcoma malignancy. Hypoxia-inducible factor-2α (HIF-2α, encoded by EPAS1) is identified as an upstream regulator that governs the malignancy gene module. HIF-2α is upregulated in high-grade chondrosarcoma biopsies and EPAS1 gene amplification is associated with poor prognosis in chondrosarcoma patients. Using tumor xenograft mouse models, we demonstrate that HIF-2α confers chondrosarcomas the capacities required for tumor growth, local invasion, and metastasis. Meanwhile, pharmacological inhibition of HIF-2α, in conjunction with the chemotherapy agents, synergistically enhances chondrosarcoma cell apoptosis and abolishes malignant signatures of chondrosarcoma in mice. We expect that our insights into the pathogenesis of chondrosarcoma will provide guidelines for the development of molecular targeted therapeutics for chondrosarcoma
URI
https://pr.ibs.re.kr/handle/8788114/8466
DOI
10.1038/s41467-020-18817-7
ISSN
2041-1723
Appears in Collections:
Center for RNA Research(RNA 연구단) > 1. Journal Papers (저널논문)
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