A druggable cascade links methionine metabolism to epigenomic reprogramming in squamous cell carcinoma

• 成果类型: Article
• 署名作者: Nam, Chehyun; Li, Li-Yan; Yang, Qian; Ziman, Benjamin; Zhao, Hua; Hu, Boyan; Collet, Casey; Jing, Pei; Lei, Qifang; Xu, Li-Yan; Li, En- Min; Koeffler, H. Phillip; Sinha, Uttam K.; Lin, De- Chen
• 署名单位: University of Southern California; Shantou University; Cedars Sinai Medical Center; Shenzhen University; University of Southern California
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14664
• DOI: 10.1073/pnas.2320835121
• 发表日期: 2024-06-25
• 关键词: cancer

摘要

Upper aerodigestive squamous cell carcinoma (UASCC) is a common and aggressive malignancy with few effective therapeutic options. Here, we investigate amino acid metabolism in this cancer, surprisingly noting that UASCC exhibits the highest methionine level across all human cancers, driven by its transporter LAT1. We show that LAT1 is also expressed at the highest level in UASCC, transcriptionally activated by UASCC - specific promoter and enhancers, which are directly coregulated by SCC master regulators TP63/ KLF5/SREBF1. Unexpectedly, unbiased bioinformatic screen identifies EZH2 as the most significant target downstream of the LAT1 - methionine pathway, directly linking methionine metabolism to epigenomic reprogramming. Importantly, this cascade is indispensable for the survival and proliferation of UASCC patient - derived tumor organoids. In addition, LAT1 expression is closely associated with cellular sensitivity to inhibition of the LAT1 - methionineEZH2 axis. Notably, this unique LAT1 - methionineEZH2 cascade can be targeted effectively by either pharmacological approaches or dietary intervention in vivo. In summary, this work maps a unique mechanistic cross talk between epigenomic reprogramming with methionine metabolism, establishes its biological significance in the biology of UASCC, and identifies a unique tumor - specific vulnerability which can be exploited both pharmacologically and dietarily.