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

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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.
Author(s)
김종욱김지혜노진경손재경신동명이지현임세슬장은주황세인
Issued Date
2021
Type
Article
Keyword
Cancer metabolismNon-small-cell lung cancer
DOI
10.1038/s12276-021-00715-7
URI
https://oak.ulsan.ac.kr/handle/2021.oak/8396
https://ulsan-primo.hosted.exlibrisgroup.com/primo-explore/fulldisplay?docid=TN_cdi_nrf_kci_oai_kci_go_kr_ARTI_9893817&context=PC&vid=ULSAN&lang=ko_KR&search_scope=default_scope&adaptor=primo_central_multiple_fe&tab=default_tab&query=any,contains,BIX01294%20inhibits%20EGFR%20signaling%20in%20EGFR-mutant%20lung%20adenocarcinoma%20cells%20through%20the%20BCKDHA-mediated%20reduction%20of%20EGFR%20levels&offset=0&pcAvailability=true
Publisher
EXPERIMENTAL AND MOLECULAR MEDICINE
Location
대한민국
Language
한국어
ISSN
1226-3613
Citation Volume
53
Citation Number
12
Citation Start Page
1877
Citation End Page
1887
Appears in Collections:
Medicine > Medicine
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