A HIF1α Regulatory Loop Links Hypoxia and Mitochondrial Signals in Pheochromocytomas

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Abstract
Pheochromocytomas are neural crest–derived tumors that arise from inherited or sporadic mutations in at least six independent genes. The proteins encoded by these multiple genes regulate distinct functions. We show here a functional link between tumors with VHL mutations and those with disruption of the genes encoding for succinate dehydrogenase (SDH) subunits B (SDHB) and D (SDHD). A transcription profile of reduced oxidoreductase is detected in all three of these tumor types, together with an angiogenesis/hypoxia profile typical of VHL dysfunction. The oxidoreductase defect, not previously detected in VHL-null tumors, is explained by suppression of the SDHB protein, a component of mitochondrial complex II. The decrease in SDHB is also noted in tumors with SDHD mutations. Gain-of-function and loss-of-function analyses show that the link between hypoxia signals (via VHL) and mitochondrial signals (via SDH) is mediated by HIF1α. These findings explain the shared features of pheochromocytomas with VHL and SDH mutations and suggest an additional mechanism for increased HIF1α activity in tumors. Pheochromocytomas (also known as paragangliomas) are highly vascular tumors that arise from mutations in a diverse and apparently unrelated group of tumor suppressor genes and oncogenes. The authors show here that three of the genes that cause hereditary pheochromocytomas have a common function. Specifically, these genes, VHL, SDHB, and SDHD, encode proteins that regulate a transcription factor known as hypoxia-inducible factor 1 subunit α (HIF1α), which helps cells adapt to hypoxia (low oxygen levels). VHL is named after its role in von Hippel-Lindau disease (VHL), an inherited disorder that predisposes individuals to pheochromocytomas and other tumors. Previous studies showed that when cells lack VHL, HIF1α is not degraded, resulting in a signal that resembles hypoxia. The authors found that loss of two genes that cause two distinct pheochromocytoma syndromes (the genes SDHB and SDHD, which encode the subunits B and D of succinate dehydrogenase, a component enzyme of the energy and respiratory system in mitochondria) also triggers a HIF1α response. The researchers further discovered that high H1F1α levels can suppress SDHB. This suggests a regulatory loop that further enhances the “hypoxia” profile of tumors. This finding provides a rational explanation for the shared features of these distinct syndromes and may be relevant for other cancers with a prominent hypoxic pattern.