Hyaluronan synthases posttranslational regulation in cancer

Hyaluronan (HA) is a critical component of cancer microenvironment that is known to increase tumor progression and aggressiveness. The synthesis of HA starts from the cytosolic precursors UDP N-acetylglucosamine and UDP-glucuronic acid. These two sugar nucleotides have several functions in addition to glycoconjugate synthesis and glucuronidation reactions, each of which can have a critical role in cancer. HA is synthesized by a family of three HA synthase (HAS) enzymes and, in this review, we described the main posttranslational modifications that are known to regulate HA metabolism. In particular, as the main HAS in adult tissues is HAS2, we focused on the role of AMPK-mediated phosphorylation and glycosylation by O-linked N-acetylglucosamine (O-GlcNAcylation) of HAS2 which mediate HAS2 inactivation and activation, respectively. HA catabolism, furnishing glucuronic acid and N-acetylglucosamine, can represent for a cancer cell a valid source of substrates to sustain complex tumor metabolism, and we highlight a presumable metabolic fate of such sugars in tumor cells.