Protein may be key to cancer’s deadly resurgences

Tumour 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.

University of California, San Francisco (UCSF), researchers working in the laboratory of Emin Maltepe, MD, PhD, associate professor of paediatrics, 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 tumours have a core composed of necrotic, or dying, cells. Ameri and colleagues concentrated on the part of tumours 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 tumour 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 mitochondrial protein called HIGD1A, enables cells to survive in the extreme environment deep in the tumour by repressing their metabolism and the production of toxic reactive oxygen species (ROS).

Key protein represses tumour growth
When the scientists engineered tumours to overexpress HIGD1A, the tumours dramatically repressed their growth, as the team reported in the 17 February issue of Cell Reports. But the overall survival of the tumour cells 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 oxygen consumption 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.

The data suggest that HIGD1A plays an important role in tumour dormancy mechanisms and may be a novel target for cancer 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 tumour cell survival in these HIF-deficient extreme environments.

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

Ameri and Maltepe conducted the study in collaboration with the laboratories of Manish Aghi, MD, PhD, associate professor of neurological surgery; Joseph F. Costello, PhD, the Karen Osney Brownstein Endowed Chair in Molecular Neuro-Oncology; and Stefanie S. Jeffrey, MD, John and Marva Warnock Professor of Surgery at Stanford School of Medicine.