DNA damage induced by human CD40 ligand mutant promotes senescence and induces demethylation of GATA4 in lung cancer

Li,Yue; Wei,Yunyan; Yuan,Weiwei; Huang,Qiqing; Zhao,Yaya; Zhao,Weihong; Xu,Wei; Wu,Jianqing

doi:10.3892/or.2018.6310

DNA damage induced by human CD40 ligand mutant promotes senescence and induces demethylation of GATA4 in lung cancer

Authors:
- Yue Li
- Yunyan Wei
- Weiwei Yuan
- Qiqing Huang
- Yaya Zhao
- Weihong Zhao
- Wei Xu
- Jianqing Wu
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Affiliations: Jiangsu Provincial Key Laboratory of Geriatrics, Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
Published online on: March 13, 2018 https://doi.org/10.3892/or.2018.6310
Pages: 2071-2080
Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The ligand of CD40, known as CD154 or CD40L, is the key to immunostimulatory and anticancer activity, but how CD40L affects cellular senescence is unclear. Thus, we studied a membrane‑stable mutant form CD40L (CD40L‑M) to explore tumor growth and cellular senescence in CD40‑positive NSCLC cells. We found that CD40L‑M‑expressing cells had senescent characteristics, including reduced cell proliferation and enlargement, increased SA‑β‑gal staining activity, and overexpression of several cell cycle regulators p53 and p21. In addition, expression of GATA4 was restored, and the NF‑κB signaling pathway was activated in the CD40L‑M‑induced senescent cells. Mechanistic analyses revealed that CD40L‑M expression triggered the ATM/Chk2 DNA damage response, which mediated cell senescence and GATA4 activation. Knockdown of GATA4 reversed CD40L‑M‑induced senescence and decreased NF‑κB activity. Thus, CD40L‑M contributes to induction of cell senescence in CD40‑positive NSCLC cells, and GATA4 is a switch to activate the NF‑κB pathway, which is positively regulated by DNA damage response (DDR) signaling kinases. Collectively, CD40L‑M‑induced senescence may be a barrier to the growth of lung cancer cells.

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