Protein may be key to cancer's deadly resurgences

Protein may be key to cancer’s deadly resurgences
The green indicates the key protein HIGD1A that slows down the metabolism of cancer cells, allowing them to hibernate and survive longterm. These mouse embryonic cells have been programmed to overexpress the protein. Credit: the Maltepe Lab

Tumor recurrence following a period of remission is the main cause of death in cancer. The ability of cancer cells to remain dormant during and following therapy, only to be reactivated at a later time, frequently with greater aggressiveness, is one of the least-understood aspects of the disease. 

UCSF researchers working in the laboratory of Emin Maltepe, MD, PhD, associate professor of pediatrics, led by associate research specialist Kurosh Ameri, PhD, have now identified a protein that plays a critical role in this process. 

Tackling Resistant Cancer Cells

Solid tumors have a core composed of necrotic, or dying, cells. Ameri and colleagues concentrated on the part of tumors that immediately surrounds these necrotic cores, which is known as the perinecrotic region.

Cancer cells in the perinecrotic region have traditionally been more difficult to eradicate than those nearer to the tumor surface, because they are deprived of both oxygen and nutrients – factors that promote resistance to therapy.

A classic regulator of cellular responses to low-oxygen conditions is the transcription factor known as hypoxia-inducible factor 1, or HIF-1. Perinecrotic regions paradoxically lack HIF-1 activity, but they retain expression of a small subset of HIF target genes.

The authors of the new study found that the protein product of one of these genes, a called HIGD1A, enables cells to survive in the extreme environment deep in the tumor by repressing their metabolism and the production of toxic (ROS).

Key Protein Represses Tumor Growth

When the scientists engineered tumors to overexpress HIGD1A, the tumors dramatically repressed their growth, as the team reported in the Feb. 17 issue of Cell Reports. But the overall survival of the was significantly enhanced, and these effects were even seen in mice that lacked the HIF-1 protein.

To discern the mechanisms behind these effects, the authors looked for interactions between HIGD1A and other mitochondrial proteins. They found that it interacted with components of the electron transport chain responsible for as well as ROS production. Expression of the HIGD1A protein reduced oxygen consumption but triggered increased mitochondrial ROS formation, which resulted in the activation of cellular antioxidant mechanisms driven by another critical metabolic regulatory protein, AMP-dependent kinase, or AMPK.

Surprisingly, the researchers found that the HIGD1A gene is not activated by hypoxia, or oxygen deprivation, in human cancers, even though the gene recruits HIF-1 to its promoter region. A lack of HIGD1A expression in response to hypoxia alone was due to increased methylation of the HIGD1A gene's regulatory regions, which could be overcome in experiments either by applying pharmacological DNA-demethylating agents, or by combined oxygen/glucose deprivation, conditions that simulate the perinecrotic environment.

These data suggest that HIGD1A plays an important role in tumor dormancy mechanisms and may be a novel target for therapy. Severe oxygen and nutrient deprivation decreases the levels of the enzyme DNA methyltransferase in multiple human cancers, allowing HIGD1A expression, and may represent a widespread mechanism enabling tumor cell survival in these HIF-deficient extreme environments.

By dissecting these mechanisms further, the researchers hope to find novel tools to target dormant and decrease rates.

Explore further

Lack of oxygen in cancer cells leads to growth and metastasis

More information: "HIGD1A Regulates Oxygen Consumption, ROS Production, and AMPK Activity during Glucose Deprivation to Modulate Cell Survival and Tumor Growth." DOI:
Journal information: Cell Reports

Citation: Protein may be key to cancer's deadly resurgences (2015, March 3) retrieved 22 September 2019 from
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Mar 03, 2015
They ignore aspects of epigenetically effected nutrient-dependent RNA-directed DNA methylation and RNA-mediated amino acid substitutions that stabilize DNA. DNA is stabilized in the organized genomes of species from microbes to man via fixation of the amino acid substitutions in the context of the pheromone-controlled physiology of reproduction.

Instead, they focus on epigenetically effected perturbed DNA stability, albeit without making any ridiculous claims about beneficial mutations and/or natural selection that theorists still seem to think lead to the evolution of cancers and new species. Thus, they take a baby step forward towards the understanding of biologically based cause and effect by framing it in the context of a protein instead of the nutrient-dependent amino acid substitutions that might otherwise have repaired the DNA.

However, this is how nutrient stress and social stress are removed from the context of epigenetically-effected physiopathology.

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