186 Stearoyl-CoA desaturase-5 is upregulated in basal cell carcinoma: A role in aberrant cell proliferation in human skin

Abstract

Stearoyl-CoA desaturase (SCD), a Δ9-desaturase that converts saturated fatty acids into monounsaturated fatty acids, is an important regulator of lipogenesis, cell proliferation and differentiation. To date, four mouse (14) and two human (1 and 5) isoforms of SCD have been identified. Human SCD-1 is abundantly expressed in lipogenic tissues, while increased expression of SCD-5 has been reported in the brain and pancreas. Importantly, both isoforms convert stearate to its unsaturated counterpart oleate. Mice lacking SCD-1 are protected from obesity and are characterized by suppressed fatty acid synthesis and enhanced oxidation. The biological function(s) of SCDs in the human skin are not well understood. Here we report that both isoforms, in particular SCD-5, is robustly expressed in human epidermal keratinocytes. Pharmacological inhibition of SCD-1 in keratinocytes resulted in induction of endoplasmic reticulum (ER) stress and activation of mTOR signaling. Parallel studies in skin specific SCD-1 KO mouse model indicated a similar increase in ER stress with activation of NF-κb and mTOR/S6 signaling. In normal keratinocytes, SCD-1 deficiency was not accompanied with significant alterations in oleate-to-stearate or palmitoleate-to-palmitate ratio. However, elevated oleate-to-stearate ratio in basal carcinoma cells compared to normal keratinocytes signified increased SCD activity in the malignant phenotype. Tissues from patients with basal cell carcinoma showed upregulated SCD-5 transcripts in tumor compared to non-lesional control skin. Intriguingly, increases in SCD-5 mRNA expression in tumor tissues were inversely proportional to SCD-1 levels. Western blot analysis validated elevated SCD-5 protein expression and activation of mTOR/S6 signaling in tumor tissues. Our studies provide novel insight into a potential regulatory loop driving aberrant cell proliferation through modulation of fatty acid metabolism in the human skin.