Alpha-aminoadipate in the saccharopine pathway promotes cancer metastasis through sumoylation of transcription machinery
Year: 2026
Type: article
Abstract: Despite studies linking metabolism and cancer, our understanding of the metabolite network that drives metastasis remains incomplete. Through a metabolic RNAi-based screen for cell invasion, we identify alpha-aminoadipate (2-AAA), the intermediate metabolite of aminoadipic semialdehyde synthase (AASS) in the saccharopine pathway, as a common pivotal factor in metastasis of human cancers. Metabolite-protein connectivity mapping reveals that 2-AAA binds to SAE1, a crucial component of the SUMO-activating enzyme E1, and enhances SAE1 recruitment to UBA2, facilitating sumoylation. 2-AAA-mediated sumoylation of the RNA polymerase subunit POLR2A then partially promotes cancer cell invasion by inducing the expression of metastasis-promoting genes, including SPG11 and KCTD7 . Targeting AASS with cetalkonium chloride, a newly identified small molecule inhibitor against AASS, attenuates cancer cell invasion and tumor metastasis. Our study highlights the mechanism by which metastasis is mediated by metabolite-driven sumoylation and indicates AASS as an effective therapeutic target for mitigating metastatic cancer progression.
Source: Nature Communications
Authors: JiHoon Kang, Jung Seok Hwang, Jaehyun Kim, Kiyoung Eun, Chaoyun Pan, Sydney Shuff, Junghui Koo, Vanessa Avalos, Melissa Gilbert-Ross, Hannah E. Bacho, Jennifer M. Robertson, Gabriel Sica, Tianna M. Espe, Sadae Hitosugi, Lingtao Jin, Conor E. Steuer, Adam I. Marcus, Cheng-Kui Qu, Andrey A. Ivanov, Taro Hitosugi, Sumin Kang
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
OpenAlex ID: W7225266783
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