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

Oncogene volume 42, pages 2521–2535 (2023)Cite this article

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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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Fig. 1: Notch activation is correlated with MDM2 expression and poor prognosis in human liposarcomas.
Fig. 2: Effect of Notch transcriptional inhibitors (IMR1 and CB103) on human LPS246 and murine mLPS1 cells.
Fig. 3: NICD is responsible for the tumorigenic potential of mLPS1 cells.
Fig. 4: Notch activation suppresses mLPS1 cell differentiation into adipocytes.
Fig. 5: Notch signaling regulates mitochondrial biogenesis and respiration in mLPS1 cells.
Fig. 6: Notch signaling regulates mLPS1 cell metabolism and PGC-1α, whose reduced expression is correlated with poor prognosis of sarcomas, and with dedifferentiated status of liposarcomas.
Fig. 7: PGC-1α expression promotes mitochondrial biogenesis and respiration in mLPS1 cells.
Fig. 8: PGC-1α expression attenuates mLPS1 cell proliferation and tumorigenesis.

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Data availability

The data supporting this publication are available in the GSE210457 repository at https://www.ncbi.nlm.nih.gov/gds/.

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Acknowledgements

This work was supported by grants from the National Cancer Institute of the US National Institutes of Health (R01CA212609) and Purdue University Center for Cancer. Research (P30CA023168). We thank the Cooperative Human Tissue Network for providing human liposarcoma samples, and the Ohio State University Comprehensive. Cancer Center for supporting human liposarcoma samples and cell lines. We also thank the Purdue University Flow cytometry core for FACS data collection, DR. Jason Hanna (Purdue Biological Sciences) for providing stock Doxorubicin solutions, and Jun Wu for technical support.

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Authors and Affiliations

  1. Department of Animal Sciences, Purdue University, West Lafayette, IN, 47907, USA

    Pei-Chieh Tien, Xiyue Chen & Shihuan Kuang

  2. Department of Comparative Pathobiology, Purdue University, West Lafayette, IN, 47907, USA

    Bennett D. Elzey

  3. Center for Cancer Research, Purdue University, West Lafayette, IN, 47907, USA

    Bennett D. Elzey & Shihuan Kuang

  4. Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center, Columbus, OH, USA

    Raphael E. Pollock

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Contributions

P-CT designed the study, performed experiments, and wrote the manuscript. XC performed RNA-seq data analysis and interpretation. BDE supported the tumor transplant studies. REP provided human samples and interpreted the results. SK conceived the project, designed the study, analyzed the data, and wrote the manuscript. All the authors have reviewed and revised the manuscript.

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Correspondence to Shihuan Kuang.

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Tien, PC., Chen, X., Elzey, B.D. et al. Notch signaling regulates a metabolic switch through inhibiting PGC-1α and mitochondrial biogenesis in dedifferentiated liposarcoma. Oncogene 42, 2521–2535 (2023). https://doi.org/10.1038/s41388-023-02768-6

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