Alpha-aminoadipate in the saccharopine pathway promotes cancer metastasis through sumoylation of transcription machinery
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.
Authors
- Taro Hitosugi (ORCID: https://orcid.org/0000-0002-2898-6831)
- Vanessa Avalos
- Junghui Koo (ORCID: https://orcid.org/0009-0008-9696-2760)
- Sumin Kang (ORCID: https://orcid.org/0000-0001-5111-0232)
- Gabriel Sica (ORCID: https://orcid.org/0000-0002-1080-2432)
- Jennifer M. Robertson (ORCID: https://orcid.org/0000-0002-1613-0091)
- Chaoyun Pan (ORCID: https://orcid.org/0000-0002-4255-9318)
- Sadae Hitosugi
- Melissa Gilbert‐Ross (ORCID: https://orcid.org/0000-0002-1960-8302)
- Andrei A. Ivanov (ORCID: https://orcid.org/0000-0001-7476-1329)
- Adam I. Marcus (ORCID: https://orcid.org/0000-0003-0484-3569)
- Jaehyun Kim
- Kiyoung Eun (ORCID: https://orcid.org/0000-0001-9769-6136)
- Sydney R. Shuff (ORCID: https://orcid.org/0000-0002-5026-3461)
- Cheng‐Kui Qu (ORCID: https://orcid.org/0000-0002-4256-8652)
- Jung Seok Hwang
- Lingtao Jin (ORCID: https://orcid.org/0009-0005-8106-3250)
- Conor E. Steuer
- Tianna Espe
- Hannah E. Bacho
- JiHoon Kang
Institutions
- Mayo Clinic (US)
- Emory University (US)
- The University of Texas at San Antonio Health Science Center (US)
- Piedmont Cancer Institute (US)
- Mayo Clinic in Arizona (US)
- Mayo Clinic in Florida (US)
- Winship Cancer Institute (US)
- Yeungnam University (KR)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-11-04
- DOI
- https://doi.org/10.1038/s41467-026-79225-x
- Primary Topic
- Ubiquitin and proteasome pathways
- Type
- article
- Field-Weighted Citation Impact
- 0.00