Hypoxia promotes histone H3K9 lactylation to enhance LAMC2 transcription in esophageal squamous cell carcinoma

Yong Zang; Aiyuan Wang; Jianji Zhang; Mingxin Xia; Zixin Jiang; Bona Jia; Congcong Lu; Chen Chen; Siyu Wang; Yingao Zhang; Chen Wang; Xinyi Cao; Ziping Niu; Chaoran He; Xue Bai; Shanshan Tian; Guijin Zhai; Hailong Cao; Yupeng Chen; Kai Zhang

doi:10.1016/j.isci.2024.110188

Hypoxia promotes histone H3K9 lactylation to enhance LAMC2 transcription in esophageal squamous cell carcinoma

iScience. 2024 Jun 5;27(7):110188. doi: 10.1016/j.isci.2024.110188. eCollection 2024 Jul 19.

Authors

Yong Zang¹, Aiyuan Wang¹, Jianji Zhang¹, Mingxin Xia¹, Zixin Jiang¹, Bona Jia¹, Congcong Lu², Chen Chen¹, Siyu Wang¹, Yingao Zhang¹, Chen Wang³, Xinyi Cao⁴, Ziping Niu¹, Chaoran He¹, Xue Bai¹, Shanshan Tian¹, Guijin Zhai¹, Hailong Cao³, Yupeng Chen^{1

5}, Kai Zhang^{1

3

6}

Affiliations

¹ The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Key Laboratory of Medical Epigenetics, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
² Frontier Center for Cell Response, College of Life Sciences, Nankai University, Tianjin 300071, China.
³ Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China.
⁴ Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, The Second Hospital of Tianjin Medical University, Tianjin, China.
⁵ Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin Medical University, Tianjin, China.
⁶ Tianjin Key Laboratory of Retinal Functions and Diseases, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin Medical University, Tianjin 300070, China.

Abstract

Hypoxia promotes tumorigenesis and lactate accumulation in esophageal squamous cell carcinoma (ESCC). Lactate can induce histone lysine lactylation (Kla, a recently identified histone marks) to regulate transcription. However, the functional consequence of histone Kla under hypoxia in ESCC remains to be explored. Here, we reveal that hypoxia facilitates histone H3K9la to enhance LAMC2 transcription for proliferation of ESCC. We found that global level of Kla was elevated under hypoxia, and thus identified the landscape of histone Kla in ESCC by quantitative proteomics. Furthermore, we show a significant increase of H3K9la level induced by hypoxia. Next, MNase ChIP-seq and RNA-seq analysis suggest that H3K9la is enriched at the promoter of cell junction genes. Finally, we demonstrate that the histone H3K9la facilitates the expression of LAMC2 for ESCC invasion by in vivo and in vitro experiments. Briefly, our study reveals a vital role of histone Kla triggered by hypoxia in cancer.

Keywords: cancer; epigenetics; proteomics; transcriptomics.