Cancer cachexia is a systemic wasting condition frequently observed in advanced malignancies and is characterized by progressive loss of adipose tissue and skeletal muscle mass. High dietary sugar (HDS), a common dietary pattern marked by excessive carbohydrate and added sugar intake, has been linked to metabolic dysfunction, enhanced tumor progression therefore aggravated cachexia.

Using the high-sugar diet (HSD) feeding model in Drosophila, we examined flies carrying oncogenic Ras activation in combination with loss of function the tumor suppressor csk or scrib. Study has shown that HSD-mediated tumor progression is sufficient to induce systemic wasting phenotypes resembling cancer cachexia. We previously showed that heterochromatin protein 1a (HP1a), an essential epigenetic regulator of heterochromatin, suppresses HDS-driven tumor growth in Drosophila cancer models. Whether HP1a-mediated heterochromatin also modulates HDS-induced cancer cachexia has not been addressed.

Here, we found that HP1a-dependent heterochromatin formation attenuated cachexia-associated defects in muscle architecture and function in both Ras/Src and Ras/scrib tumor models. Increased heterochromatin also limited lipid droplet accumulation and reduced fat loss in tumor-bearing animals. In addition, HP1a-mediated heterochromatin preserved extracellular matrix (ECM) integrity in the fat body under HDS conditions. At the mechanistic level, heterochromatin formation restrained cachectic activation of TGFβ/Mad signaling in the fat body by reducing expression of the tumor-derived TGFβ ligand glass bottom boat (Gbb). HP1a-mediated heterochromatin formation in HDS-induced tumors reduces Matrix metalloproteinase-1 (MMP1) levels, indicating decreased proteolytic activity and concomitant attenuation of TGFβ-dependent cachectic signaling.

These results indicate that HP1a-mediated heterochromatin counteracts HDS-induced cancer cachexia by maintaining muscle and adipose tissue homeostasis and by limiting fat body ECM remodeling and TGFβ signaling. The data supports an epigenetic contribution to diet-associated cancer cachexia and suggests potential targets for therapeutic intervention.