Luciferase Reporter Cell Line - PC-9

Histone H3 lysine 36 methyltransferase SET structural domain protein 2 (SETD2) is frequently mutated or missing in a wide range of human malignancies. However, the role of SETD2 in lung adenocarcinoma (LUAD) has not been thoroughly studied. In this work, researchers discovered that SETD2 was dramatically downregulated in LUAD tissues and cell lines. Functionally, high SETD2 expression dramatically reduced cancer cell proliferation by influencing the cell cycle, whereas SETD2 deficiency increased cancer cell proliferation. The researchers found a functional target gene of SETD2, CXCL1, whose expression was inversely linked with SETD2, using a combined RNA-seq and ChIP analysis. Furthermore, deleting SETD2 accelerates the development of LUAD by activating cell cycle-related proteins. Further mechanistic studies revealed that SETD2-catalyzed histone H3 lysine 36 trimethylation (H3K36me3) interacts with the CXCL1 promoter, regulating transcription and downstream signaling pathways and increasing tumor growth in vitro and in vivo. The findings demonstrate that SETD2 decreases tumor growth by reducing CXCL1-mediated cell cycle activation, implying that targeting SETD2 to modulate H3K36me3 levels and limit CXCL1 could be a potential method for treating lung adenocarcinoma.

Figure 1. The researchers cloned different truncated fragments of the CXCL1 promoter into the pGL3-basic vector and co-transfected them with SETD2-associated shRNAs into PC-9 cells. Luciferase reporter gene assay and protein detection revealed that SETD2 negatively regulates CXCL1 expression by modulating the interaction of H3K36me3 with the CXCL1 promoter. (Zhou Y, et al., 2020)