Altered ribosomes help explain how an enzyme fuels tumor growth

A new Northwestern Medicine study has identified a previously unknown mechanism by which an enzyme promotes cancer cell proliferation, establishing it as a promising therapeutic target for cancer, according to findings published in Nature Communications.

N-acetyltransferase 10 (NAT10) is a multifunctional enzyme with oncogenic properties and has been associated with multiple types of cancer, including hepatocellular carcinoma—an aggressive type of liver cancer—and acute myeloid leukemia, among others.

NAT10 is known to acetylate, or chemically modify, RNA, but whether this mechanism supports the oncogenic properties of this protein has remained uncertain, said Daniel Arango, Ph.D., assistant professor of pharmacology and a co-corresponding author of the study.

“Some conflicting evidence existed in the literature, with most studies indicating a central role of the RNA acetylation activity of this protein, while others indicated that this function was not required for tumor growth,” said Arango, who is also a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

Testing 1,900 NAT10 variants

To better understand the impact of NAT10’s molecular mechanisms in the context of cancer, the investigators used an unbiased functional genomics approach, including deep mutational scanning and nanopore sequencing of NAT10, to evaluate more than 1,900 mutants of the protein in a single assay.

“In other words, we created a library of 1,900 different versions of the protein, each version carrying a single amino acid substitution. Then you put all these versions of NAT10 to compete with each other in a proliferation assay. If one mutant affects cell proliferation, then cells carrying that mutant will disappear or drop out of the population,” Arango said.

The assay revealed that all versions of NAT10 that impaired cell proliferation clustered in the RNA helicase domain, away from the RNA acetyltransferase region.

Subsequent validation experiments, including biochemical, cellular and animal models, confirmed that the RNA helicase domain of NAT10, but not its RNA acetyltransferase activity, is required for cancer cell proliferation and tumor growth.

Ribosomes altered to favor growth

The assay also allowed the scientists to identify the downstream mechanisms by which NAT10 induces cancer cell proliferation and tumor growth.

Through its RNA helicase function, they found that NAT10 promotes the development of cancer-specific ribosomes characterized by the loss of a chemical modification, called m1acp3Y, in RNA.

Specifically, NAT10 binding to ribosomes reduces the deposition of m1acp3Y, which is commonly reduced in ribosomes of cancer cells compared with those in tumor tissues, creating a subpopulation of ribosomes that helps cancer cells grow and proliferate.

The findings highlight a previously unknown mechanism by which NAT10 promotes cancer cell proliferation and establish NAT10’s RNA helicase domain as a new potential therapeutic target for cancer.

A shift in treatment strategy

“The finding that the RNA helicase domain, rather than its RNA acetyltransferase activity, is required for tumor growth is paradigm-shifting and can lead to redirecting therapeutic strategies that aim to target this protein for cancer treatment,” Arango said.

The next steps for the research will involve using a multidisciplinary approach to translate the current findings into tailored therapeutic strategies, Arango said.

“This type of multidisciplinary work is only possible through collaborations with scientists with complementary expertise. This message is very important now more than ever,” Arango said.

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Lisa Lock

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Robert Egan

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