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Downregulation of YAP-dependent Nupr1 promotes tumor-repopulating cell growth in soft matrices

Q Jia1, W Zhou1, W Yao1

  • 1Laboratory for Cellular Biomechanics and Regenerative Medicine, Department of Biomechanical Engineering, School of Life Sciences and Technology Huazhong University of Science and Technology, Wuhan, Hubei, China.

Oncogenesis
|April 19, 2016
PubMed

Insights

Nuclear protein 1 (Nupr1) suppresses the growth of highly tumorigenic cells (TRCs). Nupr1 downregulation promotes cancer cell proliferation, suggesting its critical role in tumor progression.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Understanding the precise identity and growth regulation of malignant tumorigenic cells (TRCs) remains a challenge despite advances in cancer molecular mechanisms.
  • Tumor-repopulating cells (TRCs), a small sub-population of cancer cells, have been mechanically selected and grown in soft fibrin matrices, but their growth regulators beyond Sox2 are unclear.

Purpose of the Study:

  • To investigate the role of nuclear protein 1 (Nupr1) in regulating the growth of highly tumorigenic TRCs.
  • To elucidate the molecular mechanisms by which Nupr1 influences TRC proliferation, independent of Sox2.

Main Methods:

  • Mechanically selecting and culturing single cancer cells in soft fibrin matrices to generate TRCs.
  • Analyzing Nupr1 expression levels in TRCs from melanoma, ovarian, and breast cancer.
  • Investigating the regulation of Nupr1 by YAP, Cdc42, F-actin, and Lats1 interactions.
  • Assessing the impact of Nupr1 silencing and overexpression on TRC growth in vitro and in vivo.

Main Results:

  • Nuclear protein 1 (Nupr1) is downregulated in TRCs from melanoma, ovarian, and breast cancer.
  • Nupr1 expression is regulated by YAP nuclear translocation, which is controlled by Cdc42-mediated F-actin and Lats1 interactions.
  • Nupr1 regulates tumor suppressor p53 and negatively controls Nestin and Tert, which promote TRC growth independently of Sox2.
  • Nupr1 silencing enhances TRC growth, while Nupr1 overexpression inhibits it in culture and in immune-competent mice.

Conclusions:

  • Nupr1 acts as a suppressor of growth for highly tumorigenic TRCs.
  • Nupr1 plays a critical role in regulating cancer progression and may represent a therapeutic target.

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