Newly identified cell signaling suppressor may promote cancer, certain genetic diseases,
UT Southwestern study finds
UT Southwestern Medical Center researchers have identified a key mechanism that suppresses cellular development and may lead to several diseases, including cancer.
Defective growth of the hair-like cell signaling and sensory organelle primary cilium has been linked to a number of genetic diseases. In the study available online in Nature, UT Southwestern scientists report that a protein called OFD1 has an important role in suppressing primary cilia formation and this suppression could be released by the cellular recycling process called autophagy. By removing this protein, researchers successfully rejuvenated cilia growth.
“Dysfunctional cilia are known to underlie a number of often chronically disabling and sometimes life-threatening genetic conditions. This study provides the first possible approach to reconstitute cilia formation in cilia-lacking cells, which may help to treat several diseases,” said Dr. Qing Zhong, senior author of the study and Associate Professor of Internal Medicine and Biochemistry.
More than 20 genetic diseases known as ciliopathies have been linked to defective cilia growth, affecting an estimated 1 in 1,000 people, Dr. Zhong said. One of those diseases, oral-facial-digital syndrome 1, is a rare neurodevelopmental disorder caused by a mutation of the OFD1 gene named after the disease. Symptoms may include oral, facial, finger, and toe defects, brain abnormalities and kidney cysts.
Researchers also suspect cilia malfunction may play a critical role in cancer development. Multiple studies have revealed missing or defective cilia in human breast, ovarian, prostate, and pancreatic cancer cells.
“Quite often cancer cells have lost the ability to form cilia,” Dr. Zhong said. “Our study showed that in breast cancer cells this ability is suppressed, and after releasing this suppression, cilia began to grow. This is the first study to show that cilia defects can be reversed in human cancer cells.”
Further study is underway to determine if rejuvenated cilia in cancer cells stops or reduces cancer development – right now, this is just a hypothesis. But if true, a chemical compound that silences OFD1’s cilia suppression potentially could be developed as a valuable new anti-cancer therapy. Researchers also plan to test the effects of cilia regrowth in mouse models of ciliopathic diseases.
Dr. Zhong’s investigation evolved from his research in UT Southwestern’s Center for Autophagy Research. The study revealed how the ciliopathy protein OFD1 is degraded at locations in cells called centriolar satellites by autophagy, promoting cilia formation. Conversely, when this recycling system malfunctions due to mutations in autophagy genes, cilia formation is thwarted. Based on these observations, researchers suspect that autophagy deficiency might also cause ciliopathies.
The investigation received support from the National Cancer Institute and the American Cancer Society.
Lead author of the study is Zaiming Tang, a visiting junior researcher working in UT Southwestern’s Center for Autophagy Research and Department of Biochemistry. Researchers from Stanford University, the National Institute of Biological Sciences, Beijing, and Zhejiang University in China, and the Telethon Institute of Genetics and Medicine, and the University of Naples Federico II in Italy also participated.