Original WB Li and Kang et. al. Developmental Cell

The neurotransmitter GABA has been thought to be involved in the development of some types of cancer. Yet, the de novo synthesis of GABA and how it functions in hepatocellular carcinoma (HCC) remain unclear. Here, we report that SLC6A12 acts as a transporter of GABA and ALDH9A1 (aldehyde dehydrogenase 9 family member A1), not GAD1 (glutamate decarboxylase 1), generates GABA in human HCC. Interestingly, SLC6A12 and ALDH9A1 are upregulated during lung metastases of HCC, and depletion of either of them leads to impaired HCC metastasis. Mechanistically, GABA directly binds and stabilizes β-catenin, resulting in activated Wnt/β-catenin signaling, and thereby enhanced HCC metastasis. Reciprocally, β-catenin transcriptionally upregulates SLC6A12 to import more GABA to stabilize β-catenin. Thus, our findings identify ALDH9A1 is the major GABA synthetase in HCC, demonstrate a positive-feedback regulatory mechanism for sustaining Wnt/β-catenin signaling, and find a role for β-catenin in sensing GABA that contributes to HCC metastasis.

神经递质GABA一直被认为与某些类型癌症的发展有关。然而，GABA的从头合成及其在肝细胞癌（HCC）中的功能尚不明确。本研究报告指出，SLC6A12作为GABA和醛脱氢酶9家族成员A1（ALDH9A1）的转运蛋白，而非谷氨酸脱羧酶1（GAD1），在人类HCC中生成GABA。有趣的是，SLC6A12和ALDH9A1在HCC的肺转移期间上调，而二者中任一成分的耗竭均会导致HCC转移功能受损。从机制上讲，GABA直接结合并稳定β-连环蛋白，从而激活Wnt/β-连环蛋白信号通路，进而增强HCC的转移。反之，β-连环蛋白转录上调SLC6A12，以导入更多GABA以稳定β-连环蛋白。因此，我们的研究揭示了ALDH9A1是HCC中的主要GABA合成酶，展示了维持Wnt/β-连环蛋白信号通路的正反馈调节机制，并发现了β-连环蛋白在感知GABA、促进HCC转移中的作用。