Abstract
BackgroundHyperinsulinemia, the presence of excess insulin relative to glucose in the blood, is considered to be a poor prognostic indicator for patients with triple-negative breast cancer (TNBC). mTOR, a downstream effector of insulin, enhances mitochondrial biogenesis and activity, thereby increasing acetyl-CoA precursors. Increased acetyl-CoA can, in turn, be utilized by nuclear acetyltransferases for histone acetylation, a critical feature of genome regulation. While signaling pathways downstream of insulin have been established for sometime, the effect of insulin on chromatin remains unclear. We hypothesized that hyperinsulinemia-induced metabolic changes lead to genome-wide changes in histone acetylation in TNBC.ResultsMDA-MB-231 cells were xenografted into hyperinsulinemic and wild-type mice. Tumors in the hyperinsulinemic mice displayed elevated levels of histone acetylation compared to tumors in normal insulin conditions. We show that insulin treatment in vitro leads to global increase in chromatin-associated histone acetylation, in particular at H3K9, through the PI3K/AKT/mTOR pathway. Genome-wide analyses revealed that most promoter regions have an increase in histone acetylation upon insulin treatment. In addition, insulin induces higher levels of reactive oxygen species and DNA damage foci in cells.ConclusionsThese results demonstrate the impact of hyperinsulinemia on altered gene regulation through chromatin and the importance of targeting hyperinsulinemia-induced processes that lead to chromatin dysfunction in TNBC.
Highlights
Hyperinsulinemia, the presence of excess insulin relative to glucose in the blood, is considered to be a poor prognostic indicator for patients with triple-negative breast cancer (TNBC). mechanistic target of rapamycin (mTOR), a downstream effector of insulin, enhances mitochondrial biogenesis and activity, thereby increasing acetyl-CoA precursors
Tumors derived from the Rag/ MKR mice were significantly larger and weighed more than those derived from the MKR tumors, as previously described [34] (Fig. 1a, b)
We investigated the impact of hyperinsulinemia, an important feature of metabolic syndrome, on chromatin and gene expression changes in TNBC cells
Summary
Hyperinsulinemia, the presence of excess insulin relative to glucose in the blood, is considered to be a poor prognostic indicator for patients with triple-negative breast cancer (TNBC). mTOR, a downstream effector of insulin, enhances mitochondrial biogenesis and activity, thereby increasing acetyl-CoA precursors. MTOR, a downstream effector of insulin, enhances mitochondrial biogenesis and activity, thereby increasing acetyl-CoA precursors. We hypothesized that hyperinsulinemia-induced metabolic changes lead to genomewide changes in histone acetylation in TNBC. Metabolic syndrome is a collection of risk factors for cardiovascular disease and diabetes, and several types of cancer [1]. Multiple factors common to metabolic syndrome, including hyperinsulinemia, hyperglycemia, hyperlipidemia as well as altered adiponectin and leptin levels, can promote tumor growth and progression [2]. The insulin signaling pathway has many effectors that can promote cancer development. Insulin binding to IR leads to downstream activation of PI3K/AKT and MAPK signaling pathways [15]. The PI3K/AKT pathway has oncogenic properties and in addition induces mTOR signaling to promote cell growth [16, 17]. The PI3K/AKT pathway has oncogenic properties and in addition induces mTOR signaling to promote cell growth [16, 17]. mTOR signaling can stimulate mitochondrial biogenesis and activity, which increases TCA cycle utilization and ATP production through increased rates of oxidative phosphorylation [18]
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