MTAP loss upregulates BCAT1 in pancreatic cancer and drives branched-chain amino acid dependency.

Authors

Yuling Sheng, Lianhui Duan, Qi Liu, Yihuizhi Zhang, Yanyun Chang, Jingyu Yan, Haoyuan Tan, Zexuan Wang, Yanlin Xiao, Yiping He, Kaisheng Liu, Xin Hong, Siyuan Xia, Wenyong Zhang, Changzheng Du

Published in

Cell reports. Volume 45. Issue 10. Pages 118046. Sep 29, 2026. Epub Sep 29, 2026.

Abstract

Methylthioadenosine phosphorylase (MTAP) deficiency is prevalent in pancreatic ductal adenocarcinoma (PDAC). Herein, we reveal that MTAP loss in PDAC induces a branched-chain amino acid (BCAA) dependency by upregulating the expression of BCAA transaminase 1 (BCAT1) through DNA demethylation. We establish that BCAT1 upregulation promotes cell proliferation and migration in PDAC by fueling the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) via BCAA consumption. Moreover, the BCAA dependency contributes to a more aggressive phenotype via activation of cancer-associated pathways. In addition, the BCAT1 inhibitor BAY-069 demonstrates remarkable therapeutic efficacy in MTAP-deficient PDAC by diminishing the BCAA-facilitated OXPHOS. Finally, clinical analysis reveals an inverse correlation between MTAP and BCAT1 expression in PDAC, and high BCAT1 expression is associated with poor prognosis in patients with PDAC. Collectively, these findings identify the role of BCAT1 as a key regulator mediating metabolic reprogramming in MTAP-deficient PDAC and support BCAT1 as a potential therapeutic target.

PMID:
42814576
Bibliographic data and abstract were imported from PubMed on 01 Oct 2026.

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