BDH1‐mediated LRRC31 regulation dependent on histone lysine β‐hydroxybutyrylation to promote lung adenocarcinoma progression
Jingjing Huang,
Lu Liang,
Shiyao Jiang,
Yueying Liu,
Hua He,
Xiaoyan Sun,
Yi Li,
Li Xie,
Yongguang Tao,
Li Cong,
Yiqun Jiang
Affiliations
Jingjing Huang
The Key Laboratory of Model Animal and Stem Cell Biology in Hunan Province, Hunan Normal University Changsha Hunan China
Lu Liang
The Key Laboratory of Model Animal and Stem Cell Biology in Hunan Province, Hunan Normal University Changsha Hunan China
Shiyao Jiang
The Key Laboratory of Model Animal and Stem Cell Biology in Hunan Province, Hunan Normal University Changsha Hunan China
Yueying Liu
The Key Laboratory of Model Animal and Stem Cell Biology in Hunan Province, Hunan Normal University Changsha Hunan China
Hua He
The Key Laboratory of Model Animal and Stem Cell Biology in Hunan Province, Hunan Normal University Changsha Hunan China
Xiaoyan Sun
The Key Laboratory of Model Animal and Stem Cell Biology in Hunan Province, Hunan Normal University Changsha Hunan China
Yi Li
The Key Laboratory of Model Animal and Stem Cell Biology in Hunan Province, Hunan Normal University Changsha Hunan China
Li Xie
Department of Head and Neck Surgery Hunan Cancer Hospital, Xiangya School of Medicine, Central South University Changsha Hunan China
Yongguang Tao
Department of Pathology Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Xiangya Hospital, School of Basic Medicine, Central South University Changsha Hunan China
Li Cong
The Key Laboratory of Model Animal and Stem Cell Biology in Hunan Province, Hunan Normal University Changsha Hunan China
Yiqun Jiang
The Key Laboratory of Model Animal and Stem Cell Biology in Hunan Province, Hunan Normal University Changsha Hunan China
Abstract Lung adenocarcinoma (LUAD) is the most common form of lung cancer, with a consistently low 5‐year survival rate. Therefore, we aim to identify key genes involved in LUAD progression to pave the way for targeted therapies in the future. BDH1 plays a critical role in the conversion between acetoacetate and β‐hydroxybutyrate. The presence of β‐hydroxybutyrate is essential for initiating lysine β‐hydroxybutyrylation (Kbhb) modifications. Histone Kbhb at the H3K9 site is attributed to transcriptional activation. We unveiled that β‐hydroxybutyrate dehydrogenase 1 (BDH1) is not only conspicuously overexpressed in LUAD, but it also modulates the overall intracellular Kbhb modification levels. The RNA sequencing analysis revealed leucine‐rich repeat‐containing protein 31 (LRRC31) as a downstream target gene regulated by BDH1. Ecologically expressed BDH1 hinders the accumulation of H3K9bhb in the transcription start site of LRRC31, consequently repressing the transcriptional expression of LRRC31. Furthermore, we identified potential BDH1 inhibitors, namely pimozide and crizotinib, which exhibit a synergistic inhibitory effect on the proliferation of LUAD cells exhibiting high expression of BDH1. In summary, this study elucidates the molecular mechanism by which BDH1 mediates LUAD progression through the H3K9bhb/LRRC31 axis and proposes a therapeutic strategy targeting BDH1‐high‐expressing LUAD, providing a fresh perspective for LUAD treatment.
