Oxygen Deprivation Activates Tumor Survival Genes in Solid Tumors

HIF-1 regulates many responses to oxygen deprivation but is frequently absent in viable cells within the hypoxic perinecrotic regions of solid tumors. Cells in this region are deprived of both oxygen and nutrients, which promote their resistance to therapy.

Since Higd1a decreases tumor growth but promotes tumor cell survival in vivo, investigators at the University of California, San Francisco (USA) have examined how the HIGD1A gene becomes activated in the absence of its usual inducer, HIF-1.

They reported in the February 12, 2015, online edition of the journal Cell Reports that the human HIGD1A gene was located on chromosome 3p22.1, where many tumor suppressor genes reside. Consistent with this, the HIGD1A gene promoter was differentially methylated in human cancers, preventing its hypoxic induction. However, when hypoxic tumor cells were confronted with glucose deprivation, DNA methyltransferase activity was inhibited, enabling HIGD1A expression, metabolic adaptation, and possible dormancy induction. Under these conditions Higd1a protein was available to interact with the mitochondrial electron transport chain to repress oxygen consumption, enhance AMPK (AMP-dependent kinase) activity, and lower cellular ROS (reactive oxygen species) levels.

Studies conducted in vivo with tumor cells that had been genetically engineered to overexpress HIGD1A, demonstrated dramatically repressed tumor growth but significantly enhanced overall tumor survival, and these effects were even seen in mice that lacked the HIF-1 protein.

Based on these results, the authors suggested that, "Our findings therefore reveal important new roles for this family of mitochondrial proteins in cancer biology."

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