Inhibition of Twist1-mediated invasion by Chk2 promotes premature senescence in p53-defective cancer cells

Cell Death and Differentiation
Debasis NayakAnindya Goswami

Abstract

Twist1, a basic helix-loop-helix transcription factor is implicated as a key mediator of epithelial-mesenchymal transition (EMT) and metastatic dissemination in p53-deficient cancer cells. On the other hand, checkpoint kinase 2 (Chk2), a major cell cycle regulatory protein provides a barrier to tumorigenesis due to DNA damage response by preserving genomic stability of the cells. Here we demonstrate that Chk2 induction proficiently abrogates invasion, cell scattering and invadopodia formation ability of p53-mutated invasive cells by suppressing Twist1, indicating Chk2 confers vital role in metastasis prevention. In addition, ectopic Chk2, as well as its (Chk2) induction by natural podophyllotoxin analog, 4'-demethyl-deoxypodophyllotoxin glucoside (4DPG), strongly restrain Twist1 activity along with other mesenchymal markers, for example, ZEB-1, vimentin and Snail1, whereas the epithelial markers such as E-cadherin and TIMP-1 expression augmented robustly. However, downregulation of endogenous Chk2 by siRNA as well as Chk2 selective inhibitor PV1019 implies that 4DPG-mediated inhibition of Twist1 is Chk2-dependent. Further, mechanistic studies unveil that Chk2 negatively regulates Twist1 promoter activity and it (Chk2) interacts...Continue Reading

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Citations

Jun 9, 2019·Breast Cancer Research and Treatment·Debasis NayakAnindya Goswami
Jul 8, 2020·Acta Biochimica Et Biophysica Sinica·Jun ZhaoGuohai Zhao
Aug 23, 2018·International Journal of Oncology·Rong-Xing LiuWen-Juan Sun
Nov 18, 2018·Aging·Artem SmirnovEleonora Candi
Aug 28, 2021·Frontiers in Cell and Developmental Biology·Hua-Yang FanXin-Hua Liang

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