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DUSP6 regulates Notch1 signalling in colorectal cancer

Author

Listed:
  • Chin Wen Png

    (National University of Singapore
    National University of Singapore
    National University of Singapore)

  • Madhushanee Weerasooriya

    (National University of Singapore
    National University of Singapore
    National University of Singapore)

  • Heng Li

    (National University of Singapore
    National University of Singapore
    National University of Singapore)

  • Xiaowen Hou

    (National University of Singapore
    National University of Singapore
    National University of Singapore)

  • Fiona Yayuan Teo

    (National University of Singapore
    National University of Singapore
    National University of Singapore)

  • Shiying Huang

    (National University of Singapore
    National University of Singapore
    National University of Singapore)

  • Zheng Ser

    (Technology and Research (A*STAR))

  • Franklin Yau Kok Weng

    (National University of Singapore
    National University of Singapore
    National University of Singapore)

  • Malini Rethnam

    (National University of Singapore
    National University of Singapore)

  • Gloryn Chia

    (National University of Singapore
    National University of Singapore)

  • Radoslaw M. Sobota

    (Technology and Research (A*STAR))

  • Choon Seng Chong

    (National University of Singapore)

  • Ker-Kan Tan

    (National University of Singapore)

  • Yongliang Zhang

    (National University of Singapore
    National University of Singapore
    National University of Singapore)

Abstract

Notch1 plays various roles in cancer development, and Notch1-induced transactivation is controlled by phosphorylation of its cleaved intracellular domain. However, it is unclear whether there are phosphatases capable of dephosphorylating the cleaved Notch1 transmembrane/intracellular region (NTM) to regulate its function. Here, we show that DUSP6 can function as a phosphatase for Notch1, thereby regulating NTM stability and transcriptional activity, thus influencing colorectal cancer (CRC) development. In human CRC cells, elevated DUSP6 expression correlates with increased NTM levels, leading to enhanced CRC cell proliferation both in vitro and in vivo. High tumoral DUSP6 protein expression is associated with poorer overall CRC patient survival. In mice, DUSP6 deficiency results in reduced CRC development. Mechanistically, DUSP6 dephosphorylates phospho-Y2116, which in turn reduces NTM ubiquitination, leading to increased NTM stability and transcriptional activity. As a result, the expression of Notch1-targeted proliferation genes is increased to promote tumour cell growth.

Suggested Citation

  • Chin Wen Png & Madhushanee Weerasooriya & Heng Li & Xiaowen Hou & Fiona Yayuan Teo & Shiying Huang & Zheng Ser & Franklin Yau Kok Weng & Malini Rethnam & Gloryn Chia & Radoslaw M. Sobota & Choon Seng , 2024. "DUSP6 regulates Notch1 signalling in colorectal cancer," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-54383-y
    DOI: 10.1038/s41467-024-54383-y
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    References listed on IDEAS

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    1. Nikolaus Fortelny & Christopher M. Overall & Paul Pavlidis & Gabriela V. Cohen Freue, 2017. "Can we predict protein from mRNA levels?," Nature, Nature, vol. 547(7664), pages 19-20, July.
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