Abstract PR08: IL4 signaling increases acetyl-CoA metabolism and histone acetylation to promote breast cancer metastasis
Authors: Williams Demond , Uririr Chilesi , Fingleton Barbara 
Published: December 2020

Interleukin-4 (IL-4) has a number of well-established functions in immune cells including proliferation, and survival of lymphocytes, as well as polarization of macrophages to the pro-tumor M2 tumor associated macrophage phenotype. Many of the signaling effects of IL4 in immune cells involve regulation of metabolism such as increased glycolysis in B-lymphocytes and increased fatty acid oxidation in IL4 polarized macrophages. Despite understanding of the effects of IL4 signaling in immune cells not much is known about the consequences of IL4 signaling in tumor cells that express IL-4 Receptor (IL-4R). Previous work from our lab has shown that loss of IL-4R significantly abrogates metastasis in experimental models in mice. Thus, we wondered whether changes in metabolism downstream of IL-4 receptor activation can contribute to the metastatic phenotypes observed. Since altered metabolism has been shown to regulate the epigenetic state of cancer cells, we are examining histone modifications as a mechanism for the connections between metabolic regulation and increased metastatic capability in IL-4R expressing breast cancer cells. MDA-MB-231 and BT549 human triple negative breast cancer cell lines were treated with IL4 for various times. Samples of media from these cells were assayed for glucose and lactate. IL-4 treatment increased the consumption of glucose, and the release of lactate in IL-4R expressing breast cancer cell lines. This finding was confirmed using NBDG uptake assays. In addition, breast cancer cell lines were treated with IL-4 before undergoing biochemical fractionation to obtain nuclear lysates. These nuclear lysates were assessed for histone acetyltransferase (HAT) activity, and we observed that IL-4 treated lysates showed increased HAT activity. Western blotting was used to assess abundance of specific histone acetylation modifications and found that IL-4 increases acetylation of histone 3 lysine 9 as well as histone 3 lysine 27. In addition, we have also shown that IL-4 increases phosphorylation at serine 455 of ATP-Citrate-lyase (ACLY), an enzyme that plays a vital role in the production of nuclear and cytosolic pools of acetyl-CoA. This phosphorylation is a putative positive regulator of ACLY and its enzymatic activity. We’ve shown that treatment of IL-4R expressing cancer cells with inhibitors of HAT enzymes decreases proliferation, and clonogenic capabilities of those cells. However, IL-4 treatment is able to rescue the effects of HAT inhibition. Taken together these data suggest that the metastatic phenotype associated with IL-4 signaling in IL-4R expressing breast cancer is mediated at least partially by epigenetic modification, specifically histone acetylation.

Citation Format: Demond Williams, Chilesi Uririr, Barbara Fingleton. IL4 signaling increases acetyl-CoA metabolism and histone acetylation to promote breast cancer metastasis [abstract]. In: Abstracts: AACR Special Virtual Conference on Epigenetics and Metabolism; October 15-16, 2020; 2020 Oct 15-16. Philadelphia (PA): AACR; Cancer Res 2020;80(23 Suppl):Abstract nr PR08.