March 30, 2018

Research Probes Key Protein’s Role in Cancer Cell Growth

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Cornell researchers discover protein regulating mechanism which could be the key to eventually treating over 30 percent of all human cancers.

For more than three decades, mutant Ras proteins have been known to play a vital role in driving 95 percent of pancreatic cancers and 45 percent of colorectal cancers. With this in mind, Dr. Hui Jing and Dr. Xiaoyu Zhang, both former graduate students who worked under Professor Hening Lin, chemical biology, sought to learn more about the regulation of human cancers by studying K-Ras4a: one of the four members of the Ras protein family.

In addition to studying K-Ras4a, Zhang and Lin studied SIRT2, which is another protein that has been closely implicated in aging related diseases.

“In the basic research field, scientists still do not fully understand how SIRT2 promotes the formation of the certain types of cancers” said Zhang.

Zhang and Jing hoped that by deconstructing the mechanism by which SIRT2 brings about human cancers, they could better provide targeted therapies for treatment in the future.

For Zhang, the most challenging premise behind the research project was making the connection between the two proteins K-Ras4a and SIRT2, especially since they belong to completely different families.

“Before we started this project, the only common feature of these two proteins we knew is that they are both important in cancers” said Zhang.

In order to identify similarities between these two proteins Zhang and Jing performed different types of biochemistry and cell biology experiments.

“We encountered some technical challenges while we were trying to identify the mechanism for protein modification of K-Ras4a,” Jing said.

In order to get through these technical challenges, Jing and Zhang worked closely with Dr. Sheng Zhang at the Cornell Proteomics facility. They were able to identify that K-Ras4a is subject to lysine fatty acylation, a new protein modification that occurs after protein translation. In some cases, “K-Ras4a will activate its downstream proteins and promote cancer cell proliferation”, said Jing.

The project’s results suggest that the enzyme SIRT2 directly regulates K-Ras4a through lysine defatty acylation. The data also highlighted the biological significance of this protein modification mechanism in understanding a large portion of human cancers. More information about the work can be found here.

Although Dr. Zhang and Dr. Jing are currently conducting their postdoctoral research at the Scripps Research Institute, other lab members at the Lin Lab are working on developing a potent SIRT2 inhibitor in order to promote anti-cancer activity. Once developed, this inhibitor could be vital in treating pancreatic, colorectal, and lung cancers.