UNC researchers discover “master regulator” role for little-known protein in cancer cells

UNC researchers discover “master regulator” role for little-known protein in cancer cells click to enlarge Rajarshi Choudhury, PhD

CHAPEL HILL, N.C. – Researchers in the UNC School of Medicine found that the protein DAZAP1 plays a key role in the regulation of many genes through a process known as alternative splicing, and when highly expressed in cancer cell line experiments, DAZAP1 was shown to inhibit several types of cancer cells from dividing and moving.

The discovery, published in the journal Nature Communications, marks the first time this little-known protein has been characterized in relation to cancer development and tumor growth.

“If you knock down DAZAP1, then most of the genes involved in specific cancer cell signaling, cell death, and DNA repair are affected,” said Rajarshi Choudhury, PhD, a postdoctoral research associate in the department of pharmacology and first author of the study. “It’s a domino effect. DAZAP1 seems to be a sort of master regulator.”

The protein regulates how genes are spliced together before the genes produce the proteins that are involved in causing cancer cells to grow and divide. When there’s a lot of DAZAP1, cancer cells cease proliferating. “We’ve seen this in six different types of human cancer cell lines in the lab,” Choudhury said.

Its role as a master regulator is what makes DAZAP1 different from other proteins implicated in cancer and an exciting candidate for further research.

Choudhury image

Figure above:  Inhibition of MEK/Erk pathway affected nuclear/cytoplasmic translocation of DAZAP1. The cells were transfected with tagged DAZAP1 and hnRNP A1 and detected by corresponding antibodies. Bar, 5 μm. The percents of cells with DAZAP1localized in nucleus (N), cytoplasm (C) or both compartments (N+C) were counted and plotted in the right panel (n=80 for each sample in two independent experiments).

DAZAP1 is like a commanding officer; other proteins are like soldiers. Many cancer drugs target one of the soldier proteins that have already been expressed from a gene, have received marching orders from other proteins, and are well on their way to causing problems, such as metastasis. Potential cancer drugs that target such soldier proteins sometimes prove ineffective because in some cases cancer cells figure out how to circumvent those proteins and thus the drugs that target those proteins.

DAZAP1, though, is far up the chain of command. It helps organize the genes that will create those soldier proteins. It’s more of a decision-maker. Yet, Choudhury found that DAZAP1 can still be manipulated. His experiments suggest that certain kinds of cancer cells are able to “down regulate” DAZAP1 to allow the cancer cells to divide quickly and relocate. How the cells “down regulate” DAZAP1 is not known. In fact, how the protein becomes part of cancer cell biology isn’t well understood. That will require fully characterizing the protein and figuring out how DAZAP1 senses external signals like nutrients or growth factors that regulate its properties. This could open new avenues of research that will help scientists to better understand formation of certain cancer cell types and how they might be targeted.

(excerpt from UNC School of Medicine New article, April 29, 2014.  Read full article on SOM news site)

Read the journal article in Nature Communications.

Zefeng Wang, PhD, associate professor of Pharmacology and member of the UNC Lineberger Comprehensive Cancer Center., is senior author on the paper. Other authors include Lee M Graves, PhD, associate professor of pharmacology and member of the UNC Lineberger Comprehensive Cancer Center, postdoctoral fellow Sreerupa Ghose Roy, PhD, graduate student Yihsuan S. Tsai, and Ashutosh Tripathy, PhD, director of the UNC Macromolecular Interactions Facility. Choudhury is currently working with Michael Emanuele, PhD, at the UNC Lineberger Comprehensive Cancer Center.