|Melanoma cell lines expressing both AP2α and HIF2α exhibit poor invasive properties. Schematic illustration of AP2α, HIF1α, and HIF2α contributions to invasive capacities in melanoma cells growing under normoxic and hypoxic conditions. Click on the image to see a larger version of it.
Melanoma is the most aggressive form of skin cancer that metastasizes readily. In a recent paper in Molecular & Cellular Proteomics, a team led by Laurence Nieto at the Institute of Pharmacology and Structural Biology in France demonstrated that two hypoxia-inducible factors play a critical role in the progression of melanoma.
“The number of cases of melanoma worldwide is increasing more rapidly than any other type of cancer,” says Nieto. “Indeed, the incidence of melanoma has more than tripled in the Caucasian population over the last 20 years.” Standard cancer treatments, such as chemotherapy and radiation therapy, are unable to tackle the disease, so new therapeutic strategies are needed.
Invasive melanoma depends on the clonal selection of cells that have adapted to their microenvironment. One of the microenvironmental factors is hypoxia, a condition of oxygen shortage, which has an impact on cell transformation and tumor progression. Two hypoxia-inducible factors, HIF1 and HIF2, play a major role in the cellular adaptation to hypoxia and are overexpressed in most cancers. “In melanoma, several studies have demonstrated that HIF1 overexpression is correlated with all states of melanoma progression,” explains Nieto. “However, how HIF2 influences melanoma initiation and progression remains poorly understood.”
To better understand how HIFs affect melanoma progression, the investigators applied proteomics tools to a melanoma cell line and catalogued the binding partners of the HIF isoforms HIF1α and HIF2α. Nieto says their work is the first to describe “the whole repertoire of HIF interacting proteins. These data provide very useful material for HIF researchers by identifying new partners and demonstrating that some well-known partners are not universal.” For example, the investigators found, with their binding assays, that the P300 transcriptional co-activators, thought to be binding partners of HIFs, were poorly detected.
Most importantly, the investigators established that HIF2α interacts with the microphthalmia-associated transcription factors SOX10 and AP2α, both of which play important roles in melanoma development. The investigators found that the melanoma cells became less invasive when HIF2α was present along with AP2α.
Nieto says, “Our work underlines that as HIF protein function could be specifically modulated by several protein partners which confer opposing properties, the function of HIF1 and HIF2 must be investigated specifically in each tumor type before envisaging the use of drugs targeting these factors for cancer treatments.”