Autophagy-Mediated Clearance of Free Genomic DNA in the Cytoplasm Protects the Growth and Survival of Cancer Cells.

Mengfei Yao,Yaqian Wu,Lin Nong,Haijing Liu,Ningning Ma,Yanan Cao,Hong Zhang,Li Liang,Bo Zhang,Shuang Zhang,Yijie Chai

doi:10.3389/fonc.2021.667920

Mengfei Yao, Yaqian Wu + Show 9 more

Open Access

https://doi.org/10.3389/fonc.2021.667920

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Abstract

The cGAS (GMP-AMP synthase)-mediated senescence-associated secretory phenotype (SASP) and DNA-induced autophagy (DNA autophagy) have been extensively investigated in recent years. However, cGAS-mediated autophagy has not been elucidated in cancer cells. The described investigation revealed that active DNA autophagy but not SASP activity could be detected in the BT-549 breast cancer cell line with high micronucleus (MN) formation. DNA autophagy was identified as selective autophagy of free genomic DNA in the cytoplasm but not nucleophagy. The process of DNA autophagy in the cytosol could be initiate by cGAS and usually cooperates with SQSTM1-mediated autophagy of ubiquitinated histones. Cytoplasmic DNA, together with nuclear proteins such as histones, could be derived from DNA replication-induced nuclear damage and MN collapse. The inhibition of autophagy through chemical inhibitors as well as the genomic silencing of cGAS or SQSTM1 could suppress the growth and survival of cancer cells, and induced DNA damage could increase the sensitivity to these inhibitors. Furthermore, expanded observations of several other kinds of human cancer cells indicated that high relative DNA autophagy or enhancement of DNA damage could also increase or sensitize these cells to inhibition of DNA autophagy.

Highlights

CGAS is an enzyme that catalyzes GTP and ATP to form cyclic dinucleic 2′,3′-cGAMP to stimulate stimulator of interferon gene (STING) and activate the kinases TBK1 and IKK, inducing the production of proinflammatory factor type I interferon [1]. cGAS-STING has been identified as an innate immune mechanism, but many recent studies have shown that cGAS-STING plays a major role in the activation of the senescence-associated secretory phenotype (SASP), in which senescent cells secrete many cytokines, growth factors, proteases and chemokines acting through either autocrine or paracrine mechanisms to promote inflammation [2,3,4,5,6]
We unexpectedly found that the BT-549 breast cancer cell line with a high frequency of MN formation presented a low SASP phenotype but high autophagic activity, and subsequent experiments showed that its high DNA autophagy mediated by cGAS and cytosol-free DNA was closely related to MN formation and DNA damage, and inhibition of DNA autophagy could suppress its growth and survival
The results suggested that free cytoplasmic DNA autophagy could be mediated in a complicated process, assumedly involving cGAS binding to DNA and recognition of ubiquitinated histones by SQSTM1, respectively

Summary

Introduction

CGAS is an enzyme that catalyzes GTP and ATP to form cyclic dinucleic 2′,3′-cGAMP to stimulate stimulator of interferon gene (STING) and activate the kinases TBK1 and IKK, inducing the production of proinflammatory factor type I interferon [1]. cGAS-STING has been identified as an innate immune mechanism, but many recent studies have shown that cGAS-STING plays a major role in the activation of the senescence-associated secretory phenotype (SASP), in which senescent cells secrete many cytokines, growth factors, proteases and chemokines acting through either autocrine or paracrine mechanisms to promote inflammation [2,3,4,5,6]. CGAS is an enzyme that catalyzes GTP and ATP to form cyclic dinucleic 2′,3′-cGAMP to stimulate stimulator of interferon gene (STING) and activate the kinases TBK1 and IKK, inducing the production of proinflammatory factor type I interferon [1]. CGAS-STING has been identified as an innate immune mechanism, but many recent studies have shown that cGAS-STING plays a major role in the activation of the senescence-associated secretory phenotype (SASP), in which senescent cells secrete many cytokines, growth factors, proteases and chemokines acting through either autocrine or paracrine mechanisms to promote inflammation [2,3,4,5,6]. CGAS-STING-mediated SASP or autophagy have not been fully elucidated in cancer cells

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