BIX01294 inhibits EGFR signaling in EGFR-mutant lung adenocarcinoma cells through the BCKDHA-mediated reduction of EGFR levels

Abstract

BIX01294 (BIX), an inhibitor of G9a histone methyltransferase, has been reported to have antitumor activity against a variety of cancers. However, the molecular mechanisms underlying its anticancer effects, particularly against lung cancer, have remained unclear. Here, we report that BIX induces apoptotic cell death in EGFR-mutant non-small cell lung cancer (NSCLC) cells, but not in their wild type counterparts. Treatment with BIX resulted in a significant reduction of EGFR levels and inhibition of EGFR signaling only in the EGFR-mutant NSCLCs, leading to apoptosis. BIX also inhibited mitochondrial metabolic function and the cellular energy levels that are critical for maintaining the EGFR level. Further, BIX transcriptionally downregulated the branched-chain α-keto acid dehydrogenase (BCKDHA) transcripts that are essential for fueling the tricarboxylic acid (TCA) cycle. Interestingly, this BCKDHA downregulation was due to an inhibition of Jumanji-domain histone demethylases but not G9a histone methyltransferase. We observed that KDM3A, one of Jumanji-domain histone demethylases, epigenetically regulates the BCKDHA expression by binding to the BCKDHA gene promoter. BIX exposure also led to a significantly decreased EGFR level, causing apoptosis in EGFR-TKI (tyrosine kinase inhibitor)-resistant cell lines, that are dependent on EGFR signaling for survival. Taken together, our current data suggest that BIX triggers apoptosis only in EGFR-mutant NSCLCs via the inhibition of BCKDHA-mediated mitochondrial metabolic function.