Deciphering Cancer: The Intersection of Epigenetics, Metabolism, and Tumorigenesis

Participating Experts: Kathryn E. Wellen, PhD (UPenn) and Jason Locasale PhD (Duke)
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Epigenetic modifications to DNA and histone proteins are known to regulate metabolic gene expression, which in turn impacts metabolite levels. Conversely, the machinery responsible for modifying DNA and histones at the epigenetic level is highly sensitive to metabolites arising from cellular metabolism. Thus, the metabolic changes associated with oncogenesis may affect the epigenetic machinery, creating a feedback loop that synergistically promotes the progression of cancer. This webinar will examine how, by targeting proteins responsible for the crosstalk between epigenetics and metabolism, we may be able to develop new and effective therapeutic options for cancer treatment.
Table of Contents:
0:32 Welcome and overview
2:31 Kathryn Wellen speaker profile
3:16 Metabolism is reprogrammed in cancer
4:23 Hallmarks of metabolic reprogramming in cancer
5:54 Epigenetic alterations in cancer cells
6:48 Histone code is mediated by writers, erasers, and readers of histone marks
8:04 Metabolic enzymes that produce “ink” as another level of regulation of chromatin modifications
10:55 Three modes of metabolite regulation of chromatin modifications
14:08 Acetyl-CoA functions in metabolic and signaling roles
18:06 Acetylation of histones is limited by acetyl-CoA production in mammalian cells
20:49 Acetyl-CoA-generating enzymes are present in the nucleus
21:28 Metabolic flexibility in acetyl-CoA production
24:14 Acetyl-CoA promotes a gene set associated with DNA replication and cell cycle in glioblastoma cells
26:17 Acetyl-CoA is dynamically regulated by glucose availability
28:14 CoA impacts KATs differentially
30:21 Kras(G12D) expression increases histone acetylation in pancreas prior to tumor development
32:48 AKT promotes acetyl-CoA production and histone modification
33:13 Key future questions
35:03 Jason Locasale speaker profile
35:55 Understanding metabolism and epigenetics
38:16 Posttranslational modifications that mediate epigenetics require metabolites
40:31 Changes in glucose flux mediate key aspects of epigenetics
42:37 The methylation status of chromatin mediates gene activity
46:11 One-carbon metabolism provides a link to epigenetics through methylation
47:13 SAM and SAH provide a link from one carbon metabolism to methylation
48:28 Histone methylation responds to methionine availability in cells
52:35 Demethylases are also regulated by metabolism
56:46 IDH1/2 dehydrogenases are recurrently mutated
57:31 KG can become limiting in physiological contexts (tumor microenvironment)
1:00:58 One carbon metabolism mediates tumorigenesis through effects on DNA methylation
1:01:54 Methylation on common cancer genes can be predicted from the expression of metabolic genes
1:03:00 Questions and answers
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