A new study from scientists at Yale School of Medicine has identified N-acetyltransferase 10 (NAT10), an enzyme highly expressed in brain metastasis, as a driver of brain metastasis. NAT10 primarily functions by adding acetyl groups to RNA molecules, regulating their function, stability or translation.

In the study published in the journal Science Advances, researchers identified NAT10 as a catalyst after conducting an in vivo shRNA screen for vulnerabilities of brain metastasis. Researchers began the study knowing that emerging evidence has shown that epigenetic regulation plays a fundamental role in cancer metastasis. The study found that knockdown of NAT10 restrains cancer cell proliferation and migration in vitro, and tumor growth and brain metastasis in vivo.

“The poorly characterized RNA helicase domain of NAT10 is critical for breast cancer cell growth in vitro, while both RNA helicase and N-acetyltransferase domains are essential for primary tumor growth and brain metastasis in vivo,” the study says. “Mechanically, NAT10 promotes the expression of PHGDH and PSAT1, two enzymes for serine biosynthesis implicated in brain metastasis. Silencing PHGDH or PSAT1 in metastatic breast cancer cells inhibits their growth in the serine/glycine-limited condition, phenocopying the effects of NAT10 depletion.”

Qin Yan, PhD, professor of pathology, principal investigator of the Yan Lab at Yale, and a Yale Cancer Center member, says the findings “establish NAT10 as a key regulator of brain metastasis and nominate NAT10 as a target for treating metastasis.”

Researchers know that metastasis is responsible for 90% of cancer-associated mortality, and brain metastases are associated with the worst outcome compared to other organs. However, treatments for these patients are limited.

Studies from this group and others have shown the profound effects of epigenetic alterations on the expression of cancer-essential genes or metastasis-promoting genes, which subsequentially modulates cancer cell proliferation, metastatic capability, and the adaptation to the distal metastatic sites. However, the epigenetic dependencies of brain metastasis are largely unexplored.

The Yale study was led by co-first authors Jocelyn Chen, PhD, a former graduate student and Peng Xu, PhD, a current postdoc in the Yan Lab at Yale. Dr. Chen and Wesley Cai, MD/PhD, another former graduate student, constructed genetic screens to specifically investigate the epigenetic dependencies of breast cancer brain metastasis (BCBM). Dr. Chen and Dr. Xu established NAT10 as a driver of BCBM with extensive evidence from in vitro experiments and preclinical studies, with the help of other co-authors. They established NAT10 as a driver of BCBM through extensive in vitro and in vivo interrogations

“We demonstrated that NAT10 regulates the expression levels of PHGDH and PSAT1 in an RNA-helicase dependent manner. NAT10 promotes PHGDH and PSAT1 expression to ensure a better survival in serine/glycine limited environment, suggesting NAT10 functions as a master regulator of brain metastasis that participates in multiple steps of metastatic cascade,” the study says, later adding that “these results indicate that NAT10 N-acetyltransferase inhibitors could be used to treat breast cancer metastasis.”