BIX01294 inhibits EGFR signaling in EGFR-mutant lung adenocarcinoma cells through a BCKDHA-mediated reduction in the EGFR level

Ji Hye Kim,Se Seul Im,Eun-Ju Chang,Jaekyoung Son,Jin Kyung Rho,Dong-Myung Shin,Sein Hwang,Ji Hyeon Lee,Jongwook Kim

doi:10.1038/s12276-021-00715-7

Ji Hye Kim, Se Seul Im + Show 7 more

Open Access

https://doi.org/10.1038/s12276-021-00715-7

Copy DOI

Abstract

BIX01294 (BIX), an inhibitor of the G9a histone methyltransferase, has been reported to have antitumor activity against a variety of cancers. However, the molecular mechanisms underlying its anticancer effects, particularly those against lung cancer, remain 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 in the EGFR level and inhibition of EGFR signaling only in EGFR-mutant NSCLC cells, leading to apoptosis. BIX also inhibited mitochondrial metabolic function and decreased the cellular energy levels that are critical for maintaining the EGFR level. Furthermore, BIX transcriptionally downregulated the transcription of branched-chain α-keto acid dehydrogenase (BCKDHA), which is essential for fueling the tricarboxylic acid (TCA) cycle. Interestingly, this BCKDHA downregulation was due to inhibition of Jumanji-domain histone demethylases but not the G9a histone methyltransferase. We observed that KDM3A, a Jumonji histone demethylase, epigenetically regulates BCKDHA expression by binding to the BCKDHA gene promoter. BIX exposure also led to a significant decrease in the EGFR level, causing apoptosis in EGFR-TKI (tyrosine kinase inhibitor)-resistant cell lines, which are dependent on EGFR signaling for survival. Taken together, our current data suggest that BIX triggers apoptosis only in EGFR-mutant NSCLC cells via inhibition of BCKDHA-mediated mitochondrial metabolic function.

Highlights

Lung cancer is a leading cause of cancer death worldwide and is generally classified as small cell or non-small cell lung cancer (SCLC or NSCLC)[1]
BIX induces apoptosis only in EGFR-mutant NSCLC cells via a reduction in the EGFR level To evaluate the antitumor effects of BIX on NSCLC cell survival, we treatment. Consistent with this result, BIX had no significant effect on the extracellular acidification rate (Fig. 3b), suggesting that it has no impact on glucose metabolism
The levels of tricarboxylic acid (TCA) cycle intermediates were significantly changed upon branched-chain α-keto acid dehydrogenase (BCKDHA) knockdown (Fig. 3e), suggesting that branched-chain amino acid (BCAA) metabolism is an important source of induces apoptotic cell death in EGFR-mutant NSCLC cells in a caspase-dependent manner

Summary

Introduction

Lung cancer is a leading cause of cancer death worldwide and is generally classified as small cell or non-small cell lung cancer (SCLC or NSCLC)[1]. 80–85% of lung cancers are NSCLCs. Despite significant diagnostic and therapeutic advances in recent decades, the overall 5-year survival rate of NSCLC is still only approximately 15%2. Despite significant diagnostic and therapeutic advances in recent decades, the overall 5-year survival rate of NSCLC is still only approximately 15%2 Conventional chemotherapeutic drugs such as cis-diamminedichloroplatinum (II) (cisplatin) and paclitaxel (Taxol) are generally used for lung cancer therapy[3]. EGFR mutations are located in exons 18–21, which encode a portion of the EGFR kinase domain and include exon 19 deletions (del19) and the L858R mutation in exon 218 These mutations cause an increase in kinase activity, leading to constitutive activation of signal transduction pathways, which in turn induces cell proliferation or blocks the apoptotic response, regardless of the presence of extracellular ligands[9]

Methods

Results

Conclusion