1. Academic Validation
  2. Notch signaling regulates a metabolic switch through inhibiting PGC-1α and mitochondrial biogenesis in dedifferentiated liposarcoma

Notch signaling regulates a metabolic switch through inhibiting PGC-1α and mitochondrial biogenesis in dedifferentiated liposarcoma

  • Oncogene. 2023 Jul 11. doi: 10.1038/s41388-023-02768-6.
Pei-Chieh Tien 1 Xiyue Chen 1 Bennett D Elzey 2 3 Raphael E Pollock 4 Shihuan Kuang 5 6
Affiliations

Affiliations

  • 1 Department of Animal Sciences, Purdue University, West Lafayette, IN, 47907, USA.
  • 2 Department of Comparative Pathobiology, Purdue University, West Lafayette, IN, 47907, USA.
  • 3 Center for Cancer Research, Purdue University, West Lafayette, IN, 47907, USA.
  • 4 Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
  • 5 Department of Animal Sciences, Purdue University, West Lafayette, IN, 47907, USA. skuang@purdue.edu.
  • 6 Center for Cancer Research, Purdue University, West Lafayette, IN, 47907, USA. skuang@purdue.edu.
Abstract

Human dedifferentiated liposarcoma (DDLPS) is a rare but lethal Cancer with no driver mutations being identified, hampering the development of targeted therapies. We and Others recently reported that constitutive activation of Notch signaling through overexpression of the Notch1 intracellular domain (NICDOE) in murine adipocytes leads to tumors resembling human DDLPS. However, the mechanisms underlying the oncogenic functions of Notch activation in DDLPS remains unclear. Here, we show that Notch signaling is activated in a subset of human DDLPS and correlates with poor prognosis and expression of MDM2, a defining marker of DDLPS. Metabolic analyses reveal that murine NICDOE DDLPS cells exhibit markedly reduced mitochondrial respiration and increased glycolysis, mimicking the Warburg effect. This metabolic switch is associated with diminished expression of Peroxisome Proliferator-activated Receptor gamma coactivator 1α (Ppargc1a, encoding PGC-1α protein), a master regulator of mitochondrial biogenesis. Genetic ablation of the NICDOE cassette rescues the expression of PGC-1α and mitochondrial respiration. Similarly, overexpression of PGC-1α is sufficient to rescue mitochondria biogenesis, inhibit the growth and promote adipogenic differentiation of DDLPS cells. Together, these data demonstrate that Notch activation inhibits PGC-1α to suppress mitochondrial biogenesis and drive a metabolic switch in DDLPS.

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