The
sialyltransferase ST6GAL1 that adds α2-6 linked
sialic acids to N-
glycans of cell surface and secreted
glycoproteins is prominently associated with many human
cancers.
Tumor-native ST6GAL1 promotes
tumor cell behaviors such as invasion and resistance to cell stress and chemo- and radio-treatments. Canonically, ST6GAL1 resides in the intracellular secretory apparatus and glycosylates nascent
glycoproteins in biosynthetic transit. However, ST6GAL1 is also released into the extracellular milieu and extracellularly remodels cell surface and secreted
glycans. The impact of this non-canonical extrinsic mechanism of ST6GAL1 on
tumor cell pathobiology is not known. We hypothesize that ST6GAL1 action is the combined effect of natively expressed
sialyltransferase acting cell-autonomously within the ER-Golgi complex and
sialyltransferase from extracellular origins acting extrinsically to remodel cell-surface
glycans. We found that
shRNA knockdown of intrinsic ST6GAL1 expression resulted in decreased ST6GAL1 cargo in the exosome-like vesicles as well as decreased
breast tumor cell growth and invasive behavior in 3D in vitro cultures. Extracellular ST6GAL1, present in
cancer exosomes or the freely soluble recombinant
sialyltransferase, compensates for insufficient intrinsic ST6GAL1 by boosting
cancer cell proliferation and increasing invasiveness. Moreover, we present evidence supporting the existence novel but yet uncharacterized cofactors in the exosome-like particles that potently amplify extrinsic ST6GAL1 action, highlighting a previously unknown mechanism linking this
enzyme and
cancer pathobiology. Our data indicate that extracellular ST6GAL1 from remote sources can compensate for cellular ST6GAL1-mediated aggressive
tumor cell proliferation and invasive behavior and has great clinical potential for extracellular ST6GAL1 as these molecules are in the extracellular space should be easily accessible targets.