Page 42 - Read Online

Page 12 Qu et al. J Transl Genet Genom 2023;7:3-16 https://dx.doi.org/10.20517/jtgg.2022.16

found among theApc Min/+ lost VELs, one matches the binding motif for ELF3, and another matches a known
motif that is part of the IFN-stimulated response element (ISRE). The ISRE is a binding site for interferon
regulatory factors (IRF), which regulate interferon transcription.

DISCUSSION
Dysregulated lipid metabolism in cancer
Previous studies have shown that 15-20 weeks of HFD feeding resulted in multiple epigenetic changes in the
[5,6]
intestinal epithelium . We have previously shown that HFD promotes adenoma development inApc Min/+
[2]
mice as early as three days on HFD . Our current study shows that feeding mice an HFD causes epigenetic
and transcriptional changes within 3 days in the small intestinal epithelia. Many of these changes are
associated with genes involved in lipid metabolism. Our studies suggest that H3K27ac changes play an
essential role in mediating the upregulation of many of these genes, including pathways involved in the
synthesis, uptake, storage, and oxidation of lipids, all of which have the potential to support accelerated
tumor growth [31-33] .

Our studies indicate that the transcriptomic upregulation of many of these lipid metabolic genes is mediated
by epigenetic changes, as shown by increased H3K27ac. Since fatty acids are essential to meet energy needs
and provide the structural building blocks required for cancer cell growth, these metabolic enzymes are
often upregulated in cancer [34,35] . For example, acetyl-CoA carboxylases may rewire cancer metabolism from
glycolysis to lipogenesis to support energy demands for proliferation . Stearoyl-CoA desaturases (SCDs)
[36]
are involved in the synthesis of monounsaturated fatty acids (MUFAs) that are valuable in the formation of
cancer stem cells and the promotion of their stem properties . MUFAs amplify Wnt signaling via
[32]
stabilization of β-catenin and LRP5/6 in rodent hepatic stellate cells and tumor-initiating cells . SCD1
[37]
activity has also been shown to affect Hippo/YAP signaling by promoting the nuclear accumulation of YAP
and increasing its transcriptional activity in lung adenocarcinoma cancer stem cells in a Wnt-dependent
manner . CD36 is commonly upregulated to facilitate increased exogenous fatty acid uptake and has been
[38]
shown to play a role in tumor cell growth, metastasis, and epithelial-mesenchymal transition in multiple
cancers . These lipogenic genes are regulated in part by AMPK signaling . AMPK signaling is essential in
[31]
[27]
sensing cellular energy levels, promoting the uptake and oxidation of glucose and lipids, and inhibiting
anabolic pathways that promote cell growth when energy reserves are low. Although AMPK serves as a
tumor suppressor tied to energy regulation in non-cancer cells, it has been shown to act as a tumor
promoter in cancer cells by protecting against various stressors, including glucose starvation and
extracellular matrix detachment . HOMER analysis of the gained VELs also identified a few de novo motifs
[39]
similar to known nucleotide sequences that serve as binding sites for transcription factors involved in lipid
metabolism (PPAR-α) and cellular proliferation (Fos, Jun-B).

Dietary suppression of immune processes
HFD downregulated several genes involved in immune processes. Among these were significant
histocompatibility complex (MHC) genes involved in antigen presentation. Although MHC class II
expression and function are generally considered restricted to professional antigen-presenting cells,
intestinal stem cells (ISCs) located in the epithelium have also been shown to express high levels of MHC
class II proteins. They can capture, process, and present antigens to CD4+ T cells . Our results are
[30]
substantiated by recent reports showing that HFD dampens MHC class II expression in murine intestinal
epithelial cells, including intestinal stem cells . Since MHC-mediated activation of CD4+ T cells is vital for
[30]
tumor immunity, the loss of such MHC II expression in premalignant ISCs may enhance tumor initiation
and contribute to the acceleration of tumor progression by HFD. MHC class II expression was also shown
to be mediated by interferon-gamma signaling in the same study, and HFD was shown to downregulate
genes involved in this pathway in our study. HOMER analysis of lost VELS also identified a few de novo