Abstract
High dietary sugar (HDS) is a modern dietary concern that involves excessive consumption of carbohydrates and added sugars, and increases the risk of metabolic disorders and associated cancers. However, epigenetic mechanisms by which HDS induces tumor progression remain unclear. Here, we investigate the role of heterochromatin, an important yet poorly understood part of the epigenome, in HDS-induced tumor progression of Drosophila Ras/Src and Ras/scrib tumor systems. We found that increased heterochromatin formation with overexpression of heterochromatin protein 1a (HP1a), specifically in tumor cells, not only decreases HDS-induced tumor growth/burden but also drastically improves survival of Drosophila with HDS and Ras/Src or Ras/scrib tumors. Moreover, HDS reduces heterochromatin levels in tumor cells. Mechanistically, we demonstrated that increased heterochromatin formation decreases wingless (wg) and Hippo (Hpo) signaling, thereby promoting apoptosis, via inhibition of Yorkie (Yki) nuclear accumulation and upregulation of apoptotic genes, and reduces DNA damage in tumor cells under HDS. Taken together, our work identified a novel epigenetic mechanism by which HP1a-mediated heterochromatin formation suppresses HDS-induced tumor progression likely by decreasing wingless and Hippo signaling, increasing apoptosis, and maintaining genome stability. Our model explains that the molecular, cellular, and organismal aspects of HDS-aggravated tumor progression are dependent on heterochromatin formation, and highlights heterochromatin as a therapeutic target for cancers associated with HDS-induced metabolic disorders.
Highlights
High dietary sugar (HDS), a modern dietary concern, involves high intake of total sugars, including added sugars and free sugars
Heterochromatin formation suppresses HDS-induced developmental delay and lethality of Ras/Src and Ras/scrib tumor-bearing flies HDS (1.0 M sucrose) has been shown to increase Ras/Src tumor growth/burden in Drosophila eye/antenna discs compared to normal dietary sugar (NDS, 0.15 M sucrose) [23]
Decreasing heterochromatin formation via heterochromatin protein 1a (HP1a) knockdown by expressing HP1a-RNAi in rasG12V, HP1a-RNAi; csk−/− animals reduced the developmental delay in response to HDS compared to controls, to a lesser extent than that observed in rasG12V, HP1a; csk−/−-expressing flies (Fig. 1B, C)
Summary
High dietary sugar (HDS), a modern dietary concern, involves high intake of total sugars, including added sugars and free sugars. HDS is associated with an increased risk of metabolic disorders (e.g., type 2 diabetes) and associated cancers, which are two leading causes of death worldwide [1, 2]. HDS increases tumor growth in a variety of animal models [3]. Cancer cells tend to generate energy via the “Warburg effect”-increased glucose consumption and anaerobic glycolysis [4,5,6]. Cancer cells may alter their growth signaling and metabolic states under HDS by upregulating the wingless/Wnt pathway to increase cancer growth [7] and promoting glycolysis [8, 9], respectively. HDS can induce nucleotide imbalance, DNA damage, and oncogene KRAS mutation in cancer cells [10]. The ways in which HDSassociated epigenetic mechanisms induce tumor progression remain poorly understood
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