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Abstract Alteration in tumor progression that impact tumor aggressiveness and response to therapy (1). Tryptophan metabolism has garnered recent attention due to its involvement in the progression of multiple cancers, including breast cancer (2). Metabolism of tryptophan through the kynurenine pathway leads to the generation of nicotinamide adenine dinucleotide (NAD+) (2,3), which is essential for energy production as well as multiple processes that consume NAD+, including DNA repair and epigenetics. This de novo synthesis of NAD+ is critical for stress responses that occur during cancer progression (2,4). While the conceptual linkage of these events is well supported by the literature, it is unclear how these events are coordinately regulated and how they might meaningfully impact therapeutic outcomes given the complexity and cell type specificity of metabolic reprogramming in cancer. Our work on integrin α6β4 signaling provides compelling new insight into this regulation, its impact on epigenetics and ultimately response to select anti-cancer therapies for triple negative breast cancer (TNBC). The objective of this study is to determine how integrin α6β4 regulates tryptophan metabolism through the kynurenine pathway in TNBC and its resulting impact on invasive growth, tumor epigenetics, and response to select therapeutics. Integrin α6β4 is a laminin receptor that contributes to the organization of epithelial monolayers and permits cells to respond appropriately to their microenvironment. In cancer and during the epithelial to mesenchymal transition, integrin α6β4 moves out of hemidesmosomal plaques and drives the most aggressive tumor cell traits, including invasive growth and metastasis (5). Our work shows that a major way that integrin α6β4 promotes an invasive and metastatic phenotype is by regulating gene expression through active DNA demethylation that results upregulation of select genes that drive an invasive and metastatic phenotype (6-8). This active DNA demethylation is controlled by the base excision repair (BER) pathway that utilizes PARP1 (7), an enzyme that catalyzes NAD+ for ribosylation of its substrates (9). In our transcriptomic and DNA methylation profiling, we have uncovered that integrin α6β4 signaling leads to almost 30-fold increase in expression of indoleamine 2,3-dioxygenase (IDO1), the rate limiting enzyme in tryptophan metabolism by a potential novel mechanism that involves gene body methylation. Gene body methylation is known to enhance transcription (10,11) and associates with several histone methyl marks including H4K20 mono-methylation (H4K20me1) (12- 14) that we found is substantially upregulated with integrin α6β4 signaling. Importantly, TCGA database analysis showed that IDO1 expression correlates with integrin β4 in breast cancer patients and in TNBC patients specifically. We also find that key enzymes in the tryptophan metabolism pathway including kynureninase (KYNU) and quinolinic acid phosphoribosyltransferase (QPRT) are 20 to 30-fold higher in cells with integrin α6β4, thus suggesting integrin α6β4 enhances tryptophan metabolism toward NAD+ de novo biosynthesis. Based on these observations, our central hypothesis is that integrin α6β4 signaling epigenetically regulates the expression of key enzymes in the tryptophan metabolism pathway, which in turn, shifts the tryptophan metabolism pathway to the BER pathway and promote the invasive growth of TNBC cells.
StatusActive
Effective start/end date3/1/1712/31/26

Funding

  • National Institute of General Medical Sciences

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