Costello syndrome is a pediatric
genetic disorder linked to oncogenic germline mutations in the HRAS gene. The disease is characterized by multiple developmental abnormalities, as well as predisposition to
malignancies. Our recent observation that heart tissue from patients with
Costello syndrome showed a loss of the
glycosaminoglycan chondroitin-4-sulfate (C4S) inspired our present study aimed to explore a functional involvement of the
chondroitin sulfate (CS) biosynthesis gene
Carbohydrate sulfotransferase 11/
Chondroitin-4-
sulfotransferase-1 (CHST11/C4ST-1), as well as an impaired
chondroitin sulfation balance, as a downstream mediator of oncogenic HRAS in
Costello syndrome. Here we demonstrate a loss of C4S, as well as a reduction in C4ST-1
mRNA and
protein expression, in primary fibroblasts from
Costello syndrome patients. We go on to show that expression of oncogenic HRAS in normal fibroblasts can repress C4ST-1 expression, whereas interference with oncogenic HRAS signaling in
Costello syndrome fibroblasts elevated C4ST-1 expression, thus identifying C4ST-1 as a negatively regulated target gene of HRAS signaling. Importantly, we show that forced expression of C4ST-1 in Costello fibroblasts could rescue the proliferation and elastogenesis defects associated with oncogenic HRAS signaling in these cells. Our results indicate reduced C4ST-1 expression and
chondroitin sulfation imbalance mediating the effects of oncogenic HRAS signaling in the pathogenesis of
Costello syndrome. Thus, our work identifies C4ST-1-dependent
chondroitin sulfation as a downstream vulnerability in oncogenic RAS signaling, which might be pharmacologically exploited in future treatments of not only
Costello syndrome and other RASopathies, but also human
cancers associated with activating RAS mutations.