The switch that promotes kidney cancer progression and metastasis

| Written by sgammon
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Kidney cancer is the sixth most common cancer in adults in the United States. Clear-cell kidney cancer, or clear-cell renal cell carcinoma (CRCC)—the cells appear pale and clear under a microscope—accounts for seven out of 10 people with kidney cancer, and is the most aggressive form of the disease. Because kidney cancer does not cause symptoms until the tumor has already grown, and is very difficult to detect in a routine physical examination, approximately 25 to 30 percent of patients aren’t diagnosed until the disease is metastatic. Unfortunately, metastatic clear-cell kidney cancer is currently incurable.

A new study by Mei Koh, Ph.D., research assistant professor in our Cell Death and Survival Program, has found that a protein called hypoxia-associated factor (HAF) is activated in conditions of low oxygen (hypoxia) and triggers CRCC cells to turn on genes that cause tumor progression and metastasis. Koh and her research team study hypoxia-inducible factors (HIF)—proteins that respond to changes in available oxygen in the cellular environment. Decreased oxygen is a common feature of malignant tumors, and is known to trigger HIF proteins in a way that drives kidney-cancer progression.

“In a previous study, we showed that HAF promotes a switch from HIF-1 to HIF-2 activation. And, we knew that high levels of HIF-2 were associated with CCRC,” said Koh. “In this study, we wanted to know how kidney cancer cells make the switch from HIF-1 to HIF-2 and what this means in terms of tumor progression and morbidity.”

HIF-1 and HIF-2 are two different proteins that share about 50 percent of the same sequence, but have different functions. In CRCC, HIF-1 plays a tumor-suppressive role and is lost during tumor progression. In contrast, HIF-2 overexpression is associated with the development of CRCC.

“We found that the switch to HIF-2 is mediated by SUMOylation of HAF,” said Koh. “SUMOylation is a biological process in which a SUMO protein (small ubiquitin-related modifier) is conjugated to a target protein—such a HAF. In CRCC, when HAF undergoes SUMOylation, it binds to HIF-2 and turns on HIF-2 genes, and this is a critical step for CRCC development and morbidity. We additionally found that high HAF levels are associated with increased metastasis in animal models of CRCC, and that patients with high levels of HAF had significantly poorer prognosis.”

“The findings are important because they suggest that HAF and regulators or HAF SUMOylation may provide a novel avenue for therapy,” said Garth Powis, D.Phil., professor and director of Sanford-Burnham’s NCI-designated Cancer Center, and senior author of the paper.

“Our next step is to understand how HAF modulates the response of kidney cancer to targeted therapy, making some tumors resistant to therapy. We are also investigating peptide inhibitors of HAF and HIF-2 as a strategy to block the switch to HIF-2,” added Koh.

A link to the paper can be found at

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