Histone lactylation inhibits RARγ expression in macrophages to promote colorectal tumorigenesis through activation of TRAF6-IL-6-STAT3 signaling
- Cell Rep. 2024 Feb 27;43(2):113688. doi: 10.1016/j.celrep.2024.113688.
- 1. 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.
- 2. School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China.
- 3. Department of Bioinformatics, Suzhou Medical College of Soochow University, Soochow University, Suzhou 215123, China.
- 4. 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. Electronic address: [email protected].
- 5. 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. Electronic address: [email protected].
- 6. 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. Electronic address: [email protected].
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.