Total loss of VHL gene function impairs neuroendocrine cancer cell fitness due to excessive HIF2α activity

• 成果类型: Article
• 署名作者: Abu-Remaileh, Muhannad; Persky, Nicole S.; Lee, Yenarae; Root, David E.; Kaelin Jr, William G.
• 署名单位: Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Howard Hughes Medical Institute
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14629
• DOI: 10.1073/pnas.2410356121
• 发表日期: 2024-10-01
• 关键词: hippel-lindau gene; tumor-suppressor protein; pas domain protein; prolyl hydroxylase; belzutifan; Mutation; identification; inhibitor; product

摘要

Loss- of- function germline von Hippel-Lindau (VHL) tumor suppressor mutations cause VHL disease, which predisposes individuals to kidney cancer, hemangioblastomas, and paragangliomas. The risk that a given VHL disease family will manifest some or all these tumor types is profoundly influenced by the VHL allele it carries. For example, almost all VHL disease families that develop paraganglioma have missense VHL mutations. VHL families with null VHL alleles develop kidney cancer and hemangioblastomas without a high risk of paraganglioma. The latter is surprising because the VHL gene product, pVHL, suppresses the HIF2 transcription factor and gain- of- function HIF2 mutations are also linked to paraganglioma. Paragangliomas arise from the sympathetic or parasympathetic nervous system. Given the lack of human paraganglioma cell lines, we studied the effects of inactivating VHL in neuroblastoma cell lines, which also arise from the sympathetic nervous system. We found that total loss of pVHL function profoundly impairs the fitness of neuroblastoma cell lines in a HIF2- dependent manner both ex vivo and in vivo. This fitness defect can be rescued by pVHL variants linked to paraganglioma, but not by pVHL variants associated with a low risk of paraganglioma. These findings suggest that HIF2 activity above a critical threshold prevents the development of paraganglioma.