Downregulation of SREBP inhibits tumor growth and initiation by altering cellular metabolism in colon cancer

Yang-An Wen,B Mark Evers,Xiaopeng Xiong,Chi Wang,Heidi L Weiss,Dana L Napier,Austin T Li,Yekaterina Y Zaytseva,Emma Vallee,Tianyan Gao

doi:10.1038/s41419-018-0330-6

Abstract

Sterol regulatory element-binding proteins (SREBPs) belong to a family of transcription factors that regulate the expression of genes required for the synthesis of fatty acids and cholesterol. Three SREBP isoforms, SREBP1a, SREBP1c, and SREBP2, have been identified in mammalian cells. SREBP1a and SREBP1c are derived from a single gene through the use of alternative transcription start sites. Here we investigated the role of SREBP-mediated lipogenesis in regulating tumor growth and initiation in colon cancer. Knockdown of either SREBP1 or SREBP2 decreased levels of fatty acids as a result of decreased expression of SREBP target genes required for lipid biosynthesis in colon cancer cells. Bioenergetic analysis revealed that silencing SREBP1 or SREBP2 expression reduced the mitochondrial respiration, glycolysis, as well as fatty acid oxidation indicating an alteration in cellular metabolism. Consequently, the rate of cell proliferation and the ability of cancer cells to form tumor spheroids in suspension culture were significantly decreased. Similar results were obtained in colon cancer cells in which the proteolytic activation of SREBP was blocked. Importantly, knockdown of either SREBP1 or SREBP2 inhibited xenograft tumor growth in vivo and decreased the expression of genes associated with cancer stem cells. Taken together, our findings establish the molecular basis of SREBP-dependent metabolic regulation and provide a rationale for targeting lipid biosynthesis as a promising approach in colon cancer treatment.

Highlights

Diverse in type and underlying genetic alterations, cancers are fundamentally a disorder of cell growth and proliferation, which requires increased cellular building blocks, such as nucleic acids, proteins, and lipids[1]
The target genes of SREBPs tested here are known to involved in cholesterol uptake and biosynthesis (including LDR receptor (LDLR), HMG-CoA reductase (HMGCR), and HMG-CoA synthase (HMGCS)) as well as fatty acid synthesis (including fatty acid synthase (FASN), acetylCoA carboxylase (ACACA), and stearoyl CoA desaturase (SCD))
SREBPs decreases cell proliferation and stemness in colon cancer cells, we investigated the functional effects of SREBP-mediated lipid biosynthesis in controlling tumor growth in vivo

Summary

Introduction

Diverse in type and underlying genetic alterations, cancers are fundamentally a disorder of cell growth and proliferation, which requires increased cellular building blocks, such as nucleic acids, proteins, and lipids[1]. To cope with these elevated requirements cancer cells undergo major metabolic modifications[2,3]. There has been increasing interest in cancer cell metabolism as a means to understand the functional distinction between transformed and normal cells and to provide critical and how lipogenic pathways are regulated. Three SREBP isoforms, SREBP1a, SREBP1c, and SREBP2, have been identified in mammalian cells that control distinct but overlapping lipogenic transcriptional programs[7,8,9].

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Conclusion