SLC13A3 is a major effector downstream of activated β-catenin in liver cancer pathogenesis

Wennan Zhao, Xue Wang, Lifeng Han, Chunze Zhang, Chenxi Wang, Dexin Kong, Mingzhe Zhang, Tong Xu, Gen Li, Ge Hu, Jiahua Luo, Sook Wah Yee, Jia Yang, Andreas Stahl, Xin Chen () and Youcai Zhang ()
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Wennan Zhao: Tianjin University
Xue Wang: University of California Berkeley
Lifeng Han: Tianjin University of Traditional Chinese Medicine
Chunze Zhang: Tianjin Union Medical Center
Chenxi Wang: Tianjin University of Traditional Chinese Medicine
Dexin Kong: Tianjin Medical University
Mingzhe Zhang: Tianjin University
Tong Xu: Tianjin University
Gen Li: Tianjin University
Ge Hu: Tianjin University
Jiahua Luo: Tianjin University
Sook Wah Yee: University of California
Jia Yang: University of California
Andreas Stahl: University of California Berkeley
Xin Chen: University of Hawaii Cancer Center
Youcai Zhang: Tianjin University

Nature Communications, 2024, vol. 15, issue 1, 1-21

Abstract: Abstract Activated Wnt/β-catenin pathway is a key genetic event in liver cancer development. Solute carrier (SLC) transporters are promising drug targets. Here, we identify SLC13A3 as a drug-targetable effector downstream of β-catenin in liver cancer. SLC13A3 expression is elevated in human liver cancer samples with gain of function (GOF) mutant CTNNB1, the gene encoding β-catenin. Activation of β-catenin up-regulates SLC13A3, leading to intracellular accumulation of endogenous SLC13A3 substrates. SLC13A3 is identified as a low-affinity transporter for glutathione (GSH). Silencing of SLC13A3 downregulates the leucine transporter SLC7A5 via c-MYC signaling, leading to leucine depletion and mTOR inactivation. Furthermore, silencing of SLC13A3 depletes GSH and induces autophagic ferroptosis in β-catenin-activated liver cancer cells. Importantly, both genetic inhibition of SLC13A3 and a small molecule SLC13A3 inhibitor suppress β-catenin-driven hepatocarcinogenesis in mice. Altogether, our study suggests that SLC13A3 could be a promising therapeutic target for treating human liver cancers with GOF CTNNB1 mutations.

Date: 2024
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DOI: 10.1038/s41467-024-51860-2

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