PO-229 The fatty acid desaturase SCD1 as crucial factor for tumour progression in colon cancer

Abstract

IntroductionAberrant activation of lipogenesis is a hallmark of cancer metabolism. However, the functional contribution of lipids to tumorigenesis is still uncovered. We analysed the clinical implication of key enzymes of fatty acid synthesis and processing, including FASN (fatty acid synthase), fatty acid elongase 6 (ELOVL6), the master transcription factor of lipid synthesis, SREBP1 (sterol regulatory element binding protein 1) and steaoryl-CoA desaturase 1 (SCD1). SCD1 is essential for the production of mono-unsaturated fatty acids (MUFAs) and crucially involved in colon cancer, suggested by our previous expression profiling data. To investigate its functional role, we generated SCD1 deficient colon cancer cells.Material and methodsSCD1, SREBP1, FASN and ELOVL6 were quantified by qPCR in 78 patients with stage III colon cancer, and clinical and prognostic significance was assessed by Kaplan-Meier analysis. SCD1 and SREBP1 were further analysed on protein level. SCD1-deficiency was implemented in colon cancer cells HCT116 by the CRISPR-Cas9 system. Mass spectrometry (MS) analysis was used to analyse the activity of SCD1; cell proliferation and survival of the SCD1 deficient clones were compared to parental cells.Results and discussionsExpression of SCD1 and FASN was highly significantly increased in tumours, whereas SREBF1 and ELOVL6 were significantly reduced. However, SCD1 and SREBP1 were upregulated in tumour tissue on protein level and their mRNA was significantly co-expressed. SCD1 was significantly associated with tumour grading and worse post-operative survival, and elevated expression of FASN and ELOVL6 with increased metastatic relapse.SCD1 deficiency was verified by DNA sequencing and immunoblotting, and MS analysis confirmed the deprivation of MUFAs. KO of SCD1 led to significantly decreased cell proliferation and survival under normal growth conditions, which was even more pronounced under reduced serum. This was fully rescued by addition of the SCD1 product oleate, suggesting that SCD1 is necessary for growth and survival especially in the absence of exogenous lipids.ConclusionSCD1, FASN and ELOVL6 are negative prognostic markers in stage III colon cancer. Functionally, SCD1 is essential for cell survival under serum depletion. Together, these data suggest that the cell-autonomous synthesis of fatty acid species in cancer cells is due to reduced access to exogenous lipids. Enhanced lipogenesis rises the requirement for the production of MUFAs by SCD1, e.g., to maintain survival and circumvent lipotoxicity.