University of North Carolina Lineberger Comprehensive Cancer Center scientist Antonio “Tony” Amelio, PhD, is not necessarily looking for the “smoking gun” of cancer biology, or one single cause of cancer. Instead, he’s looking into how a family of newly described proteins involved in the cellular stress response can cause a complex ripple effect of changes within cells that contribute to cancer development and progression.
A review in Trends in Cancer led by Amelio, who is an assistant professor in the UNC Schools of Medicine and Dentistry, explores the role of a group of cellular signaling integrators called cAMP-regulated transcriptional co-activators, or CRTCs.
These proteins help cells cope with normal stressors due to physiologic imbalances, such as low levels of blood sugar, by allowing them to respond and adapt by helping cells turn genes on and off to re-establish balance. The review describes how these proteins, and genetic mutations that affect their function, play significant and largely unexplored roles in a broad array of cancers types.
“These are an unappreciated group of regulators within our cells that form part of the incredibly intricate signaling machinery,” Amelio said. “But given the vast number of genes they’re capable of regulating, they likely play critical roles at every level of the tumorigenic process. That’s something important to keep in mind: tumorigenesis is a process. Early events initiate changes that urge development of the tumors, but later events promote the progression to metastasis and resistance to drug treatments. At every one of those stages, a different type of stress is imposed upon the cancer cell that requires orchestration of a complex series of molecular changes. And CRTCs enable cancer cells to adapt to these stresses during the transition between each different stage.”
Like a group of sentries waiting on guard, CRTCs are normally stationed in the cell’s cytoplasm outside of the cell’s central control center, the nucleus, Amelio said. When triggered, they can rush into the nucleus and drive changes to help the cell adapt. They are part of a system that allows cells to sense hormone and environmental stress signals, and respond by helping to reprogram the cell’s genes. Known as “transcriptional co-activators,” CRTCs bind to another protein called CREB that directly acts on the DNA to turn “on” the expression of certain genes.
“Cells are equipped with this ability to sense a remarkable array of cues, ranging from nutrient status to mechanical forces, and to then respond,” Amelio said. “This molecular plasticity, through gene expression reprogramming, enables normal cells to adapt in such a way that the next time the stress is imposed upon them, they are equipped to deal with it more favorably.”
There are approximately 20,000 different genes in the human genome, and CREB is known to act on a significant percentage – possibly about 10 percent. These genes are involved in directly regulating cell survival and metabolism, but in some cases these CRTC-regulated genes are themselves master transcriptional regulators that amplify the response by “switching on” even more genes, Amelio said, so the role that CRTCs play, by initially acting on CREB, can be quite profound.
Research led by the Amelio Lab has shown how mutations can affect CRTCs behavior. In some cancers, Amelio described how they can be dysregulated, always actively turning adaptive-response genes on.
“Normally, CRTCs live out in the cytosol, so they are physically separated in space and time at a subcellular level,” Amelio said. “Only through specific cues can they move into the nucleus and bind to CREB. But in cancer, this normally highly orchestrated, specific regulation of CRTCs is broken down such that those specific signaling cues that tell the CRTCs to move to the nucleus are no longer required. Rather, they’re always in the nucleus bound to CREB, where they’re constantly turning these adaptive-response genes on that normally should only be on for very short periods of time.”
One of the ways that CRTCs are known to be involved in a cancer called mucoepidermoid carcinoma, the most common salivary cancer, is through a chromosome break that causes CRTCs to become fused to another section of genetic code, creating an unnatural fusion protein. Amelio and his collaborators explain how that fusion could be involved in cancer development.
But in the review, they also describe how the mutations in CRTCs can have different effects. Depending on cell-type context, mutation in CRTCs can help inactivate what are normally tumor suppressive activities, namely in blood cancers, while in other types of cancer, mutations drive tumor promoting functions. The review describes what is known about the possible cancerous effects of mutations affecting these dynamic signaling proteins in lung, esophageal, and blood among other cancers.
“We see accumulation of mutations throughout these cellular signaling integrators, and in many different cancers,” Amelio said. “What we don’t know is: Are any of these mutations relevant to the function of CRTCs in cancer, or are they red herrings, passenger mutations that don’t do anything? What we highlight though is that there are many mutations that occur, and some of them occur at sites that regulate normal functions such as subcellular localization, but there is probably room to discover other mutations that are involved in tumorigenesis, and perhaps reveal novel physiologic functions of the CRTC protein family in the process.”
Amelio said one goal of his lab is to discover the role, if any, that CRTCs are playing in other head and neck cancers.
In addition to Amelio, other authors of the review included Jason Tasoulas, DMD, Laura Rodon, PhD, Frederic J. Kaye, MD, and Marc Montminy, MD, PhD.
The research was supported by the Dental Foundation of North Carolina, the University Cancer Research Fund, and a NIH/NCI Howard Temin Pathway to Independence Award in Cancer Research.