title: Downregulation of YAP-dependent Nupr1 promotes tumor-repopulating cell growth in soft matrices.
abstract: Despite decades of significant progress in understanding the molecular mechanisms of malignant tumorigenic cells, it remains elusive what these tumorigenic cells are and what controls the growth of these malignant cells. Recently, we have mechanically selected and grown highly malignant and tumorigenic tumor-repopulating cells (TRCs), a small sub-population of cancer cells, by culturing single cancer cells in soft fibrin matrices. However, it is unclear what regulates TRC growth besides Sox2. Here we show that nuclear protein 1 (Nupr1), a protein independent of Sox2, is downregulated in TRCs of melanoma, ovarian cancer and breast cancer cultured in soft fibrin matrices. Nupr1 expression depends on nuclear translocation of YAP that is enriched at the Nupr1 promoter sites; YAP is controlled by Cdc42-mediated F-actin and Lats1 interactions. Nupr1 regulates tumor-suppressor p53 and negatively regulates Nestin and Tert that are independent of Sox2 and promote TRC growth. Silencing Nupr1 increases TRC growth and Nupr1 overexpression inhibits TRC growth in culture and in immune-competent mice. Our results suggest that Nupr1 is a suppressor of growth of highly tumorigenic TRCs and may have a critical role in cancer progression.
authors.affiliation: Laboratory 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.
authors.forename: Q
authors.initials: Q
authors.lastname: Jia
authors.affiliation: Laboratory 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.
authors.forename: W
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Laboratory 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.
authors.forename: W
authors.initials: W
authors.lastname: Yao
authors.affiliation: Laboratory 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.
authors.forename: F
authors.initials: F
authors.lastname: Yang
authors.affiliation: Laboratory 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.
authors.forename: S
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Mechanical Science and Engineering, College of Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
authors.forename: R
authors.initials: R
authors.lastname: Singh
authors.affiliation: Laboratory 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.
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.affiliation: Laboratory 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.
authors.forename: J J
authors.initials: JJ
authors.lastname: Chen
authors.affiliation: Laboratory 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.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Laboratory 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.
authors.forename: F
authors.initials: F
authors.lastname: Wei
authors.affiliation: Laboratory 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.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Laboratory 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.
authors.forename: H
authors.initials: H
authors.lastname: Jia
authors.affiliation: Laboratory 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.|Department of Mechanical Science and Engineering, College of Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
authors.forename: N
authors.initials: N
authors.lastname: Wang