The de novo synthesis of GABA and its gene regulatory function control hepatocellular carcinoma metastasis

The neurotransmitter gamma-aminobutyric acid (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 that aldehyde dehydrogenase 9 family member A1 (ALDH9A1), not glutamate decarboxylase 1 (GAD1), 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 R-catenin, resulting in activated Wnt/R-catenin signaling, and thereby enhancing HCC metastasis. Reciprocally, R-catenin transcriptionally upregulates SLC6A12 to import more GABA to stabilize R-catenin. Thus, our findings identify ALDH9A1 as the major GABA synthetase in HCC, demonstrate a positive-feedback regulatory mechanism for sustaining Wnt/R-catenin signaling, and reveal a role for R-catenin in sensing GABA, which contributes to HCC metastasis.