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

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

Research output: Contribution to journalArticlepeer-review

144 Scopus citations

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.

Original languageEnglish
Article number265
JournalCell Death and Disease
Volume9
Issue number3
DOIs
StatePublished - Mar 1 2018

Bibliographical note

Publisher Copyright:
© 2018 The Author(s).

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

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