Exosomal 4EBP1 promotes head and neck cancer progression via regulating mitochondrial fission

Abstract

Head and neck cancer (HNC) is the sixth most common cancer around the globe with raised incidence and mortality. Despite the advancement in diagnostic and therapeutic approaches the burden of HNC has not reduced. Therefore, investigation on key molecular mechanisms that contributes to the progression of HNC is required to identify promising therapeutic targets. Exosomes are nanosized vesicles and recently emerged as a carrier of tumorigenic proteins essential for cancer progression. However, the role of exosomal proteins in HNC progression remains largely unclear. Eukaryotic Initiation Factor 4E-Binding protein 1 (4EBP1) regulates the protein synthesis and plays a crucial role in the progression of different forms of cancer. Our current study revealed that 4EBP1 is carried in human serum exosomes and upregulated in HNC serum exosomes than healthy controls (HC) and we observed that coculturing the 4EBP1 upregulated HNC serum exosomes (HNC Exo) promoted the growth and migration of HEp-2 cells. Further, we examined the underlying mechanism by knockdown of 4EBP1 in HEp-2 cells (4EBP1 KD). Our results showed that knockdown of 4EBP1 have suppressed the migration and progression of cancer cells. Mechanistically, knockdown of 4EBP1 downregulated mitochondrial fission modulators DRP1 and FIS1 and attenuated the migration of HNC cancer cells by suppressing TGFβ and upregulating PTEN. Together our findings suggest that 4EBP1 is upregulated in circulating exosomes and promotes HNC progression via modulating mitochondrial fission and could be a potential therapeutic target for HNC.