FYN-mediated phosphorylation of BCKDK at Y151 promotes GBM proliferation by increasing the oncogenic metabolite N-acetyl-L-alanine.

ABSTRACT

Branched chain α-keto acid dehydrogenase kinase (BCKDK) is a key enzyme involved in the metabolism of branched-chain amino acids (BCAAs). Its potential as a therapeutic target and prognostic factor for a variety of cancers has been widely reported. In this study, we investigated the expression of BCKDK in clinical glioma samples and found that BCKDK was significantly overexpressed in glioblastoma (GBM) and was associated with its poor prognosis. We further found that BCKDK is phosphorylated by tyrosine protein kinase Fyn at Y151, which increases its catalytic activity and stability, and demonstrate through in vivo and in vitro experiments that BCKDK phosphorylation promotes GBM cell proliferation. In addition, we found that the levels of the metabolite N-acetyl-L-alanine (NAAL) in GBM cells with high BCKDK were higher than those in the silencing group, and silencing or inhibition of BCKDK promotes the expression of ACY1, an enzyme that catalyzes the hydrolysis of NAAL into acetic acid and alanine. Exogenous addition of NAAL can activate the ERK signaling pathway and promote the proliferation of GBM cells. Taken together, we identified a novel mechanism of BCKDK activation and found NAAL is a novel oncogenic metabolite. Our study confirms the importance of the Fyn-BCKDK-ACY1-NAAL signalling axis in the development of GBM and suggests that p-BCKDK (Y151) and NAAL can serve as potential predictors of GBM progression and prognosis.