DUSP6 Regulates Notch1 Signalling in Colorectal Cancer

Overview

Journal Nat Commun

Specialty Biology

Date 2024 Nov 21

PMID 39572549

Authors

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 Chong

Ker-Kan Tan

Yongliang Zhang

Affiliations

Soon will be listed here.

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.

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