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Fatty Acid Desaturase-1 (FADS1) or delta 5 desaturase (D5D) is a rate-limiting enzyme involved in the biosynthesis of long-chain polyunsaturated fatty acids (LC-PUFAs), i.e., arachidonic acid (ARA) and eicosapentaenoic (EPA). These LC-PUFAs and their metabolites play essential and broad roles in cancer cell proliferation, metastasis, and tumor microenvironment. However, the role of FADS1 in cancers remains incompletely understood. Utilizing The Cancer Genome Atlas (TCGA) database, we explored the role of FADS1 across different cancer types using multiple bioinformatics and statistical tools. Moreover, we studied the impact of a FADS1 inhibitor (D5D-IN-326) on proliferation of multiple cancer cell lines. We identified that FADS1 gene is a predictor for cancer survival in multiple cancer types. Compared to normal tissue, the mRNA expression of FADS1 is significantly increased in primary tumors while even higher in metastatic and recurrent tumors. Mechanistically, pathway analysis demonstrated that FADS1 is associated with cholesterol biosynthesis and cell cycle control genes. Interestingly, FADS1 expression is higher when TP53 is mutated. Tumors with increased FADS1 expression also demonstrated an increased signatures of fibroblasts and macrophages infiltration among most cancer types. Our in vitro assays showed that D5D-IN-326 significantly inhibited cell proliferation of kidney, colon, breast, and lung cancer cell lines in a dose-dependent manner. Lastly, single nucleotide polymorphisms (SNPs) which are well-established expression quantitative trait loci (eQTLs) for FADS1 in normal human tissues are also significantly correlated with FADS1 expression in tumors of multiple tissue types, potentially serving as a marker to stratify cancer patients with high/low FADS1 expression in their tumor tissue. Our study suggests that FADS1 plays multiple roles in cancer biology and is potentially a novel target for precision cancer treatment.

Polyunsaturated fatty acid (PUFA) plays an important role in cancer biology. Fatty acid desaturase1 (FADS1) is a key rate-limiting enzyme in omega-3 and omega-6 PUFA metabolism. We aim to investigate the association between FADS1 and survival outcomes among cancer patients. Univariable and multivariable Cox regression models were performed for FADS1 mRNA expression levels on disease-free survival (DFS) and overall survival (OS) using The Cancer Genome Atlas (TCGA) public datasets. We also investigated the pathways associated with altered FADS1 expression in the TCGA dataset. A FADS1 inhibitor (D5D-IN-326) was used to study the proliferation in vitro in 6 different cancer cell lines. FADS1-shRNA knockdown system was introduced in the renal cell carcinoma (RCC) 786-O cell line to further study the signaling pathway associated with proliferation. Transcriptomic, metabolomic, and lipidomic profiles of stable cell lines were studied. Our analysis showed that among all cancer patients (N=11,490), those with a higher FADS1 mRNA expression in their tumor have a significantly worse DFS and OS (p.value <0.001 and 0.01, respectively). This association was particularly significant in RCC subtypes. Pathway analysis demonstrated that cell cycle and DNA replication were significantly enriched as the top pathways associated with FADS1 expression. Administration of FADS1 inhibitor compound 326 decreased cell proliferation in cell lines of several major cancers in a dose-dependent manner. The proliferation result was confirmed in RCC FADS1 knockdown model. RNA-seq analysis of FADS1 knockdown stable cells also showed downregulation of DNA biosynthesis, cell division, and cell proliferation. In our metabolomic study, 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR) was significantly reduced in FADS1 knockdown (KD) cells which may be attributed to altered purine metabolism (p-value < 0.001). As we expected, the total omega-6 and omega-3 fatty acids were lower in KD cells. We further identified lower P38 phosphorylation in KD cells which is consistent with lower cell proliferation. These results suggest that FADS1 overexpression is prognostic to lower survival in cancer patients via changing cancer metabolism, which is potentially mediated via altering cell proliferation through MAPK pathway. This study has a potential to discover a new mechanism of cancer biology and develop a novel precision treatment for cancer patients. The detailed causal relationship is warranted for continued investigation. Citation Format: Gioia Heravi, Hyejeong Jang, Seongho Kim, Wanqing Liu. Fatty acid desaturase 1 (FADS1) is associated with cancer survival via altering cell growth and can be a novel drug target for cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3370.