Histone lactylation inhibits RARγ expression in macrophages to promote colorectal tumorigenesis through activation of TRAF6-IL-6-STAT3 signaling
Xiu-Ming Li,
Yun Yang,
Fu-Quan Jiang,
Guang Hu,
Shan Wan,
Wen-Ying Yan,
Xiao-Shun He,
Fei Xiao,
Xue-Mei Yang,
Xin Guo,
Jun-Hou Lu,
Xiao-Qin Yang,
Jun-Jie Chen,
Wen-Long Ye,
Yue Liu,
Kuang He,
Han-Xiao Duan,
Yu-Jia Zhou,
Wen-Juan Gan,
Feng Liu,
Hua Wu
Affiliations
Xiu-Ming Li
Department of Pathology, Medical Center of Soochow University and Suzhou Medical College of Soochow University and YongDing Clinical Institute of Soochow University, Soochow University, Suzhou 215123, China
Yun Yang
Department of Pathology, Medical Center of Soochow University and Suzhou Medical College of Soochow University and YongDing Clinical Institute of Soochow University, Soochow University, Suzhou 215123, China
Fu-Quan Jiang
School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China
Guang Hu
Department of Bioinformatics, Suzhou Medical College of Soochow University, Soochow University, Suzhou 215123, China
Shan Wan
Department of Pathology, Medical Center of Soochow University and Suzhou Medical College of Soochow University and YongDing Clinical Institute of Soochow University, Soochow University, Suzhou 215123, China
Wen-Ying Yan
Department of Bioinformatics, Suzhou Medical College of Soochow University, Soochow University, Suzhou 215123, China
Xiao-Shun He
Department of Pathology, Medical Center of Soochow University and Suzhou Medical College of Soochow University and YongDing Clinical Institute of Soochow University, Soochow University, Suzhou 215123, China
Fei Xiao
Department of Bioinformatics, Suzhou Medical College of Soochow University, Soochow University, Suzhou 215123, China
Xue-Mei Yang
Department of Pathology, Medical Center of Soochow University and Suzhou Medical College of Soochow University and YongDing Clinical Institute of Soochow University, Soochow University, Suzhou 215123, China
Xin Guo
Department of Pathology, Medical Center of Soochow University and Suzhou Medical College of Soochow University and YongDing Clinical Institute of Soochow University, Soochow University, Suzhou 215123, China
Jun-Hou Lu
Department of Pathology, Medical Center of Soochow University and Suzhou Medical College of Soochow University and YongDing Clinical Institute of Soochow University, Soochow University, Suzhou 215123, China
Xiao-Qin Yang
Department of Bioinformatics, Suzhou Medical College of Soochow University, Soochow University, Suzhou 215123, China
Jun-Jie Chen
School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China
Wen-Long Ye
Department of Pathology, Medical Center of Soochow University and Suzhou Medical College of Soochow University and YongDing Clinical Institute of Soochow University, Soochow University, Suzhou 215123, China
Yue Liu
Department of Pathology, Medical Center of Soochow University and Suzhou Medical College of Soochow University and YongDing Clinical Institute of Soochow University, Soochow University, Suzhou 215123, China
Kuang He
Department of Pathology, Medical Center of Soochow University and Suzhou Medical College of Soochow University and YongDing Clinical Institute of Soochow University, Soochow University, Suzhou 215123, China
Han-Xiao Duan
Department of Pathology, Medical Center of Soochow University and Suzhou Medical College of Soochow University and YongDing Clinical Institute of Soochow University, Soochow University, Suzhou 215123, China
Yu-Jia Zhou
Department of Pathology, Medical Center of Soochow University and Suzhou Medical College of Soochow University and YongDing Clinical Institute of Soochow University, Soochow University, Suzhou 215123, China
Wen-Juan Gan
Department of Pathology, Medical Center of Soochow University and Suzhou Medical College of Soochow University and YongDing Clinical Institute of Soochow University, Soochow University, Suzhou 215123, China; Corresponding author
Feng Liu
Department of Pathology, Medical Center of Soochow University and Suzhou Medical College of Soochow University and YongDing Clinical Institute of Soochow University, Soochow University, Suzhou 215123, China; Corresponding author
Hua Wu
Department of Pathology, Medical Center of Soochow University and Suzhou Medical College of Soochow University and YongDing Clinical Institute of Soochow University, Soochow University, Suzhou 215123, China; Corresponding author
Summary: Macrophages are phenotypically and functionally diverse in the tumor microenvironment (TME). However, how to remodel macrophages with a protumor phenotype and how to manipulate them for therapeutic purposes remain to be explored. Here, we show that in the TME, RARγ is downregulated in macrophages, and its expression correlates with poor prognosis in patients with colorectal cancer (CRC). In macrophages, RARγ interacts with tumor necrosis factor receptor-associated factor 6 (TRAF6), which prevents TRAF6 oligomerization and autoubiquitination, leading to inhibition of nuclear factor κB signaling. However, tumor-derived lactate fuels H3K18 lactylation to prohibit RARγ gene transcription in macrophages, consequently enhancing interleukin-6 (IL-6) levels in the TME and endowing macrophages with tumor-promoting functions via activation of signal transducer and activator of transcription 3 (STAT3) signaling in CRC cells. We identified that nordihydroguaiaretic acid (NDGA) exerts effective antitumor action by directly binding to RARγ to inhibit TRAF6-IL-6-STAT3 signaling. This study unravels lactate-driven macrophage function remodeling by inhibition of RARγ expression and highlights NDGA as a candidate compound for treating CRC.
