Combined inhibition of EZH2 and the autotaxin-LPA-LPA2 axis exerts synergistic antitumor effects on colon cancer cells.

Autotaxin (ATX), also known as ENPP2, is the key enzyme in lysophosphatidic acid (LPA) production. LPA acts on its receptors on the cell membrane to promote cell proliferation and migration, and thus, the ATX-LPA axis plays a critical role in tumorigenesis. Clinical data analysis indicated that in colon cancer, there is a strong negative correlation between the expression of ATX and EZH2, the enzymatic catalytic subunit of polycomb repressive complex 2 (PRC2). Here, we demonstrated that ATX expression was epigenetically silenced by PRC2, which was recruited by MTF2 and catalyzed H3K27me3 modification in the ATX promoter region. EZH2 inhibition is a promising strategy for cancer treatment, and ATX expression is induced in colon cancer cells by EZH2 inhibitors. With both EZH2 and ATX as targets, their combined inhibition exerted synergistic antitumor effects on colon cancer cells. In addition, LPA receptor 2 (LPA2) deficiency significantly enhanced the sensitivity to EZH2 inhibitors in colon cancer cells. In summary, our study identified ATX as a novel PRC2 target gene and found that cotargeting EZH2 and the ATX-LPA-LPA2 axis may be a potential combination therapy strategy for colon cancer.

Hypoxia Increases ATX Expression by Histone Crotonylation in a HIF-2α-Dependent Manner.

Autotaxin (ATX), the key enzyme that generates lysophosphatidic acid (LPA) from lysophosphatidylcholine (LPC), is involved in tumorigenesis through the ATX-LPA axis and is regarded as a valuable target in tumor therapy. Hypoxia is a major feature of solid tumors and contributes to tumor development with striking alterations in the gene expression profile. Here, we show that hypoxia induces ATX expression in a hypoxia-inducible factor (HIF) 2α-dependent fashion in human colon cancer SW480 cells. HIF-2α is directly bound to specific hypoxia response elements (HREs) in the ATX promoter. Under hypoxic conditions, knockout or inhibition of ATX suppressed the migration of SW480 cells, which could be rescued by the addition of LPA, suggesting that the induction of ATX during hypoxia promotes cancer cell migration through the ATX-LPA axis. Further studies showed that ATX expression was induced by HIF-2α through recruiting p300/CBP, which led to crotonylation but not acetylation of histone H3 in the ATX promoter region during hypoxia. Moreover, elevation of cellular histone crotonylation levels could induce ATX expression under normoxic conditions. In conclusion, our findings reveal that ATX is induced in SW480 cells during hypoxia by histone crotonylation in a HIF-2α-dependent manner, while as a novel mechanism of ATX expression regulation, the upregulation of ATX expression by histone crotonylation is not confined to hypoxia.