Pyruvate kinase M2 interacts with nuclear sterol regulatory element-binding protein 1a and thereby activates lipogenesis and cell proliferation in hepatocellular carcinoma

J Biol Chem. 2018 Apr 27;293(17):6623-6634. doi: 10.1074/jbc.RA117.000100. Epub 2018 Mar 7.

Abstract

Dysregulation of lipid metabolism is common in cancer cells, but the underlying mechanisms are poorly understood. Sterol regulatory element-binding proteins (SREBPs) stimulate lipid biosynthesis through transcriptional activation of lipogenic enzymes. However, SREBPs' roles and potential interacting partners in cancer cells are not fully defined. Using a biochemical approach, we found here that pyruvate kinase M2 (PKM2) physically interacts with the nuclear form of SREBP-1a (nBP1a), by binding to amino acids 43-56 in nBP1a. We also found that PKM2 activates SREBP target gene expression and lipid biosynthesis by stabilizing nBP1a proteins. Using a competitive peptide inhibitor to block the formation of the SREBP-1a/PKM2 complex, we observed that this blockade inhibited lipogenic gene expression. Of note, nBP1a phosphorylation at Thr-59 enhanced the binding to PKM2 and promoted cancer cell growth. Moreover, we show that PKM2 phosphorylates Thr-59 in vitro Lastly, in human patients with hepatocellular carcinoma, nBP1a phosphorylation at Thr-59 was negatively correlated with clinical outcomes. Together, our results reveal that nBP1a/PKM2 interaction activates lipid metabolism genes in cancer cells and that Thr-59 phosphorylation of SREBP-1a plays an important role in cancer cell proliferation.

Keywords: PKM2; SREBP-1a; cell proliferation; gene transcription; hepatocellular carcinoma; lipid metabolism; lipid synthesis; lipogenesis; liver cancer; pyruvate kinase; sterol regulatory element–binding protein.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / metabolism*
  • Carcinoma, Hepatocellular / pathology
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Proliferation*
  • Gene Expression Regulation, Neoplastic
  • HEK293 Cells
  • Hep G2 Cells
  • Humans
  • Lipogenesis*
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism*
  • MCF-7 Cells
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism*
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Sterol Regulatory Element Binding Protein 1 / genetics
  • Sterol Regulatory Element Binding Protein 1 / metabolism*
  • Thyroid Hormone-Binding Proteins
  • Thyroid Hormones / genetics
  • Thyroid Hormones / metabolism*

Substances

  • Carrier Proteins
  • Membrane Proteins
  • Multiprotein Complexes
  • Neoplasm Proteins
  • Sterol Regulatory Element Binding Protein 1
  • Thyroid Hormones