Abstract
Unsaturated fatty acids are critical in promoting colon tumorigenesis and its stemness. Stearoyl-CoA desaturase-1 (SCD1) is a rate-limiting lipid desaturase associated with colon cancer cell proliferation and metastasis control. This study aims to evaluate the effects of SCD1 inhibition on colon cancer spheroid growth in a three-dimensional cell culture system. An analysis of clinical data showed that increased SCD1 gene expression in colon tumors was negatively correlated with the prognosis. A chemical inhibitor of SCD1, CAY10566, inhibited the growth of colon cancer cells in both monolayer and sphere cultures. In addition, oleic acid administration—a monounsaturated fatty acid generated by the action of SCD1—prevented the suppression of sphere formation by CAY10566. RNA-sequencing data from 382 colon tumor patient samples obtained from the Cancer Genome Atlas database showed that 806 genes were SCD1-associated genes in human colon cancer. Correlation analysis identified the master regulator of lipid homeostasis sterol regulatory element-binding protein 2 (SREBP2) as a prominent transcription factor, whose expression was positively correlated with SCD1 in human colon cancer. SCD1 knockdown using siRNA in colon cancer samples, suppressed SREBP2 gene expression, providing direct evidence that SREBP signaling is under the control of SCD1 in these cells. Pathway analysis in the Ingenuity Pathways Analysis platform showed that SCD1 expression positively correlated with genes involved in multiple pathways, including lipid synthesis and incorporation, cell proliferation, and tissue tumorigenesis. Further network analysis revealed a central role for Myc in the network hierarchy of the SCD1-correlated genes. These findings suggested that SCD1 inhibition would be an effective strategy for suppressing colon cancer spheroid growth, partly through downregulating SREBP-mediated lipid and cholesterol metabolism and Myc signaling.
Highlights
Colon cancer, a well-characterized inflammation-driven disease, is the third leading cause of cancer-related deaths worldwide, with more than one million new cases reported each year [1]
We recently showed that Stearoyl-CoA desaturase-1 (SCD1) is upregulated in cancer stem cells (CSCs)-like cell populations compared with non-CSC populations in human liver cancer cell lines [12,13]
Using the PrognoScan database [22], Kaplan–Meier estimates of the proportion of colon cancer patients who survived over 15 years, showed that patients with high SCD1 gene expression in tumors had significantly lower survival rates (Figure 1b)
Summary
A well-characterized inflammation-driven disease, is the third leading cause of cancer-related deaths worldwide, with more than one million new cases reported each year [1]. These outcomes are mainly due to its poor prognosis, where long term treatment leads to patients acquiring resistance to therapy. The major cause of colon cancer therapy failure is the emergence of tumor-driving cells or cancer stem cells (CSCs), which possess high plasticity and a mesenchymal-like phenotype [3]. New therapies based on understanding the molecular mechanisms underlying colon CSC regulation are needed
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