Normal editing functions of a stem cell enzyme called ADAR1 (Adenosine Deaminase Acting on RNA-1) are hijacked by pre-malignant cells, resulting in a series of molecular consequences that promote malignant transformation, dormant cancer stem cell generation and resistance to treatment, according to a study conducted at University of California San Diego School of Medicine. Detecting the copy-editing function of the RNA-editing enzyme ADAR1, which is active in more than 20 tumor types, may provide a detection method for early malignancies and represent a new target to treat cancer resistance.
Double-stranded RNA-specific adenosine deaminase is an enzyme that in humans is encoded by the ADAR gene, which stands for adenosine deaminase acting on RNA. Adenosine deaminases acting on RNA (ADAR) regulate gene expression by modifying nucleotides within double stranded RNA molecules, serving as fundamental editors in the development of new stem cells. However, the enzyme is also activated in several cancers, including leukemia, breast and liver cancers.
The study, published in the January issue of Cancer Cell, is led by senior author Catriona Jamieson, deputy director of the Sanford Stem Cell Clinical Center and deputy director of the UC San Diego Moores Cancer Center.
“We were able to illuminate the abilities of ADAR1 to ‘hyper-mutate’ tumor suppressor RNAs in leukemia and, at the same time, edit the microRNA aimed at targeting the tumor suppressor RNA. This enzyme turns on cancer resistance via a domino effect on RNA instead of DNA,” said first author Qingfei Jiang, assistant project scientist in Jamieson’s lab.
Jamieson characterized RNA editing as tweaking basic genetic blueprints, not fundamentally rewriting them. Nonetheless, the results might be dramatic. “One result of detection of malignant RNA editing could be exposing dormant cancer stem cells that often escape therapies that target dividing cells, which leads to therapeutic resistance and disease relapse, and also highlight ADAR as a potentially tractable target for cancer stem cell elimination,” said Jamieson.
Source: Science Daily