Our previous data supported a role for the
Stearoyl-CoA desaturase (SCD5) in protection against
malignancy, whereby it appears to functionally modify
tumor stroma impairing
tumor spread. SCD5 is significantly expressed in primary
melanoma, but becomes barely detectable at
tumor advanced stages. Looking for the regulatory mechanisms underlying SCD5 reduced expression during
melanoma progression, we demonstrated a significantly lower stability of SCD5
protein as well as the direct targeting of SCD5
mRNA by the oncogenic miR-221&222 in metastatic cell lines. Moreover, our results indicated the existence of a negative feedback loop between SCD5 and miR-221&222, in good agreement with their opposite functions. Also, we showed how SCD5 re-expression and the direct supplementation of its main product
oleic acid (OA) can drive advanced
melanoma cell lines toward differentiation and reversion of the epithelial-mesenchymal (EMT)-like process, eventually inducing a less malignant phenotype. Indeed, SCD5 re-established the sensitivity to
all-trans retinoic acid in A375M metastatic
melanoma, associated with increased levels of
Tyrosinase,
melanin production and reduced proliferation. As evidenced by the correct modulation of some key
transcription factors, SCD5 managed by favoring a partial mesenchymal-to-epithelial (MET) transition in in vitro studies. Interestingly, a more complete MET, including
E-cadherin re-expression correctly localized at cell membranes, was obtained in in vivo xenograft models, thus indicating the requirement of direct contacts between
tumor cells and the surrounding microenvironment as well as the presence of some essential factors for SCD5 complete function.