Zinc Deficiency Linked to Lung Cancer Through Hedgehog Signaling

Zinc Deficiency Linked to Lung Cancer Through Hedgehog Signaling

A biomolecular signaling pathway long associated with lung cancer is under investigation at Rensselaer Polytechnic Institute. The laboratory of Dr. Chunyu Wang, an associate professor in biological sciences at Rensselaer, identified that Hedgehog signaling can contribute to cancer in patients deficient for the nutrient zinc.

“Hedgehog is critical to normal development, but in adults the pathway, if reactivated, may lead to uncontrolled cell growth and proliferation in cancer,” said Dr. Wang, in a news release from Rensselaer. “Our paper suggests a link between zinc deficiency and activation of the Hedgehog pathway in many diseases where zinc deficiency and Hedgehog activation co-exist.”

The link between zinc, Hedgehog, and lung cancer is described in the group’s research article entitled “Zinc Inhibitis Hedgehog Autoprocessing,” which was published online in Journal of Biological Chemistry. To actively regulate cell growth and development, Hedgehog precursor protein must be cleaved into two parts through a self-catalytic event known as autoprocessing. The cleavage event is blocked by zinc binding, meaning that a zinc deficiency allows cleavage of Hedgehog into the signaling domain and the catalytic domain.

To conduct the study, the research group at Rensselaer was led by Dr. Wang and lead author Lingyun Li, a fourth-year graduate student in Dr. Wang’s laboratory. The team used techniques to characterize zinc-Hedgehog binding and Hedgehog autoprocessing. There was a strong correlation between low zinc availability and Hedgehog signaling in primary rat astrocyte (supporting brain cell) culture.

“Normally, in adults, zinc will inhibit the production of the Hedgehog ligand, and therefore inhibit the Hedgehog pathway,” said Dr. Wang. “But if there is a zinc deficiency, the pathway can be activated due to enhanced production of Hedgehog ligand. We show that zinc inhibits this autoprocessing reaction from the precursor to the ligand, providing an additional mechanism of how zinc deficiency may promote cancer development.”

This explains why zinc deficiency can be a hallmark of lung cancer, other cancers, and autism. Before this study, there was no clear indication why zinc deficiency was so important. “This is something that nobody else has shown before,” said Dr. Wang. “Zinc and Hedgehog are essential and extremely versatile biomolecules; linking these two will have profound implications for normal physiology and disease.”

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