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

Abstract

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.

p53 deficiency mediates cisplatin resistance by upregulating RRM2 and crotonylation of RRM2K283 through the downregulation of SIRT7

“…Liao M et al reported the relationship between histone H3K27 crotonylation and DNA damage of colon cancer ( Liao et al, 2022 ). Qu M et al revealed a novel mechanism of histone crotonylation-mediated ATX expression regulation by in a HIF-2α-dependent manner in a colon cancer SW480 cells ( Qu et al, 2023 ). Compared with the three researches, we find a new crotonylated protein RRM2, which K283 site crontonylation contributes to cisplatin resistance.…”

“…The level of nonhistone ENO1-Kcr is elevated in colorectal cancer tissues, and ENO1 K420Cr has been shown to stimulate the growth, migration and invasion of colorectal cancer cells in vitro ( Hou et al, 2021b ). Qu ( Qu et al, 2023 ) et al reported that p300/CBP-mediated Kcr plays a role in the induction of hypoxia by ATX in SW480 cells. Liao ( Liao et al, 2022 ) et al reported a decrease in the level of H3K27cr, which may be facilitated by SIRT6 during DNA damage in colon cancer.…”

The Emerging Role of LPA as an Oncometabolite

“…LPAR5 also interacts with cannabinoid receptor 2 (CB2) to activate AKT signalling and subsequently induce migration and proliferation [92]. Hypoxic colon cancer cells activate HIF2α, which binds hypoxia response elements (HREs) in the ATX promoter to induce the upregulation of ATX expression by histone H3 crotonylation and promote cell migration [93]. Non-alcoholic steato-hepatitis (NASH) is a condition that can promote the development of liver tumours.…”