Epigenetic regulation of metabolism is critical to maintain cellular homeostasis in
response to cellular demands and resources. Changes in the microenvironment impact
functions of epigenetic regulatory enzymes and metabolic balance must maintained to
avoid metabolic reprogramming and tumor progression [1]. Epigenetic regulatory proteins
with catalytic functions include histone “writers” or “erasers”, which effect post-translational
modifications (PTMs) of histones or non-histone proteins; chromatin remodelers, fueled
by ATP to alter chromatin structure; and, enzymes that methylate DNA or reverse DNA
methylation. Genes encoding key factors in metabolic signaling pathways are regulated
by the activities of these enzymes, which remodel or modify chromatin. Additionally,
epigenetic regulatory enzymes themselves serve as environmental sensors by relying
on available metabolites as cofactors. For example, mutations in IDH1/IDH2, which
encode isocitrate dehydrogenases of the tricarboxylic acid (TCA) cycle, are associated
with low-grade gliomas, adult de novo acute myeloid leukemias and lymphomas. Mutant
IDH1/2 exhibit gain-of-function by catalyzing conversion of α-ketoglutarate (α-KG)
to 2-hydroxy glutarate (2-HG) at 100-fold higher levels than found in normal cells.
2-HG is a competitive inhibitor of α-KG-dependent dioxygenases, including TET2, which
acts in reversal of DNA methylation, and Jumonji-C-domain-containing histone demethylases,
which alter histone PTMS; either of which may disrupt regulated gene expression [2].
In addition to epigenetic regulatory enzymes that act as sensors of cellular metabolites
and/or directly alter chromatin structure of genes that encode metabolic enzymes,
proteins known as “histone readers” serve as relay switches in regulatory networks,
including metabolism. Histone readers have specific domains that bind defined “signatures”
of histone PTMs and act as platforms for recruitment of transcription factors, mediators
or additional epigenetic response factors to chromatin. Our laboratory showed that
histone reader Tripartite motif-containing protein 24 (TRIM24) not only negatively
regulates p53 as an E3-ubiquitin ligase [3] but also interacts with and recruits transcription
factors, such as estrogen receptor, to chromatin via a tandem plant homeodomain (PHD)
and Bromodomain that binds unmethylated lysine 4 and acetylated lysine 23 of histone
H3 (H3K4me0/H3K23ac) [4]. More recently, we found that ectopic expression of TRIM24
promoted oncogenic transformation of immortalized human mammary epithelial cells (TRIM24-iHMECs)
and efficient growth of intermediate to high-grade xenograft tumors [5]. Molecular
analysis of TRIM24-iHMECs revealed a TRIM24-dependent glycolytic and TCA cycle gene
expression signature, which led to increased glucose uptake. Gene Set Enrichment Analysis
revealed the glucose transport pathway as one of the top 10 pathways positively correlated
with TRIM24 expression in human breast tumors (n = 1008) from the TCGA database. Interestingly,
Seahorse analysis showed both ECAR (measure of glycolysis) and OCR (measure of OXPHOS)
were elevated in TRIM24-iHMECs. This is unlike a conventional Warburg effect of unrestrained,
aerobic glycolysis but consistent with recent reports of cancers that exploit OXPHOS
or a mixture of glycolysis and OXPHOS for energy production [6].
In addition to its functions as a histone reader, TRIM24 is an E3-ubiquitin ligase
that targets p53 for protein degradation. Tumor suppressor p53 plays key roles in
glycolysis, OXPHOS, glutamine metabolism, lipid metabolism and antioxidant defense
to impact cellular metabolism and redox balance [7]. We surveyed both p53-positive
and -negative breast cancer-derived cell lines to assess p53-dependence of TRIM24-regulated
metabolic response and found that GLUT1, ACO1, IDH1 and IDH2, which encode important
players in glycolysis and TCA cycle, were TRIM24-activated in MCF7, SKBR3 and MDAMB231
cells despite their varied p53 status. This may be explained by our finding that TRIM24
directly regulates these genes, as well as another important player in oncogenesis
and metabolism: c-myc. Our unpublished chromatin immunoprecipitation analyses show
direct binding of TRIM24 to the upstream regulatory regions of c-myc, GLUT1, IDH1
and IDH2, concomitant with activation of transcription.
Given the clinical correlates in breast cancer patients and apparent oncogenic effects
on metabolism that we reported in human mammary epithelial cells, one might expect
that loss of TRIM24 in mouse models would oppose tumor development. However, complete
loss of Trim24, either globally or conditionally in the liver, caused spontaneous
hepatic steatosis and ultimately hepatocellular carcinoma in animals fed normal chow.
With loss of Trim24 expression, hepatocytes increased expression of lipase and inflammation
signaling genes and repressed de novo lipogenesis, steroid and lipid metabolism and
transport. The hepatic accumulation of lipids, fibrosis and infiltration of inflammatory
macrophages recapitulated parameters of human nonalcoholic fatty liver disease (NAFLD)
and non-obese-NASH [8]. Whether this outcome is the result of tissuespecific shifts
in transcription factors that collaborate with TRIM24, an altered collection of TRIM24
target genes and/or a tissue-specific response to regulated p53 levels is unknown
at this time. Clearly, additional mouse models, especially those with conditional
over expression of Trim24, and manipulation of diet, along with mechanistic studies
of functional domains and intersecting pathways, are needed to determine how epigenetic
variables and tissue-specificity dictate metabolic reprogramming by TRIM24.