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

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 and Jin-Hong Kim ()
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Hyeonkyeong Kim: Center for RNA Research, Institute for Basic Science
Yongsik Cho: Center for RNA Research, Institute for Basic Science
Hyeon-Seop Kim: Center for RNA Research, Institute for Basic Science
Donghyun Kang: Center for RNA Research, Institute for Basic Science
Donghyeon Cheon: College of Natural Sciences, Seoul National University
Yi-Jun Kim: Ewha Womans University College of Medicine
Moon Jong Chang: Seoul National University College of Medicine, Boramae Hospital
Kyoung Min Lee: Seoul National University Bundang Hospital
Chong Bum Chang: Seoul National University Bundang Hospital
Seung-Baik Kang: Seoul National University College of Medicine, Boramae Hospital
Hyun Guy Kang: Orthopedic Oncology Clinic, Specific Organs Cancer Branch, Research Institute and Hospital, National Cancer Center
Jin-Hong Kim: Center for RNA Research, Institute for Basic Science

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-18817-7

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