Cell signaling suppressor may promote cancer, variety of genetic diseases

By Debbie Bolles

Dr. Qing Zhong (left) and Zaiming Tang
Dr. Qing Zhong (left) and Zaiming Tang have identified a key mechanism that suppresses growth of a cellular component called primary cilium, which has been linked to several genetic diseases.

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 primary cilium, a hair-like signaling and sensory organelle located on the surface of cells, has been linked to a number of genetic diseases. In the study, published in the Oct. 10, 2013, issue of Nature, UT Southwestern scientists report that a specific protein, OFD1, has an important role in suppressing primary cilia formation and that this suppression could be released by the cellular recycling process called autophagy. By removing OFD1, 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 cells that lack cilia, which may help to treat several diseases,” said Dr. Qing Zhong, Associate Professor of Internal Medicine and Biochemistry and senior author of the study.

More than 20 genetic diseases known as ciliopathies have been linked to defective cilia growth and affect 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 mutation of the OFD1 gene. Symptoms may include oral, facial, finger, and toe defects; brain abnormalities; and kidney cysts.

Researchers also suspect cilia malfunction may play an important 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. 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 investigate the hypothesis that rejuvenated cilia in cancer cells stops or reduces cancer development. If true, then a chemical compound that silences OFD1’s cilia suppression could be developed as a valuable new anti-cancer therapy.

Dr. Zhong’s investigation also revealed how the ciliopathy protein OFD1 is degraded at locations in cells, called centriolar satellites, by autophagy, thereby 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 study, which was done in UT Southwestern’s Center for Autophagy Research, 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 the Center for Autophagy Research and the Department of Biochemistry. Scientists from Stanford University, the University of California, Berkeley; the National Institute of Biological Sciences; Beijing, Zhejiang University in China, Telethon Institute of Genetics and Medicine in Italy, and the University of Naples Federico II in Italy also participated.