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Chaetocin induces endoplasmic reticulum stress response and leads to death receptor 5-dependent apoptosis in human non-small cell lung cancer cells

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Abstract

Epigenetic abnormalities are associated with non-small cell lung cancer (NSCLC) initiation and progression. Epigenetic drugs are being studied and in clinical trials. However, the molecular mechanism underlying the apoptosis by the epigenetic agents remains unclear. SUV39H1 is an important methyl-transferase for lysine 9 on histone H3 and usually related to gene transcriptional suppression, and chaetocin acts as the inhibitor of SUV39H1. We demonstrated here that chaetocin effectively suppressed the growth of multiple lung cancer cells through inducing apoptosis in a death receptor 5 (DR5)-dependent manner. Chaetocin treatment activated endoplasmic reticulum (ER) stress which gave rise to the up-regulation of ATF3 and CHOP. Furthermore, ATF3 and CHOP contributed to the induction of DR5 and subsequent apoptosis. When SUV39H1 was silenced with siRNA, the expression of ATF3, CHOP and DR5 was elevated. Thereafter, knockdown of SUV39H1 induced apoptosis in NSCLC cells. In summary, chaetocin pharmacologically inhibits the activity of SUV39H1 which provokes ER stress and results in up-regulation of ATF3 and CHOP, leading to DR5-dependent apoptosis eventually. These findings provide a novel interpretation on the anti-neoplastic activity of epigenetic drugs as a new therapeutic approach in NSCLC.

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Abbreviations

DR5:

Death receptor 5

TRAIL:

TNF-related apoptosis-inducing ligand

HMT:

Histone methyl-transferases

CHOP:

CCAAT/enhancer-binding protein homologous protein

GADD153:

Growth arrest and DNA damage gene 153

ATF3:

Activating transcription factor 3

ER stress:

Endoplasmic reticulum stress

UPR:

Unfolded protein response

PERK:

Pancreatic ER kinase (PKR)-like endoplasmic reticulum kinase

ATF6:

Activating transcription factor 6

IRE1:

Inositol-requiring enzyme-1

BiP:

Binding protein/glucose-regulated protein (GRP)78

p-eIF2α:

Phosphorylated α subunit of eukaryotic translational initiation factor 2

PARP:

Poly(ADP-ribosyl) polymerase

SRB:

Sulforhodamine B

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Acknowledgments

This work was supported by Grants from the National Natural Science Foundation of China (81472686, 31371402, 31171332), the National Key Basic Research Program of China (2013CB910903) and Shandong Provincial Program for Science and Technology development (2014GSF118067).

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    Authors and Affiliations

    1. Shandong University School of Life Sciences, Rm103, South Bldg, 27 Shanda South RD, Jinan, 250100, China

      Xianfang Liu, Sen Guo, Xiangguo Liu & Ling Su

    2. Department of Otolaryngology Head and Neck Surgery, Provincial Hospital Affiliated to Shandong University, Jinan, China

      Xianfang Liu

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    1. Xianfang Liu
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    Correspondence to Ling Su.

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    Xianfang Liu and Sen Guo have contributed equally to this work.

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    Supplementary Fig. S1

    Chaetocin inhibits SUV39H1 activity in NSCLC cells. The indicated lung cancer cells were treated with 50, 100, 200 nmol/l chaetocin for 24 h. Then the SUV39H1 activity in the cells was evaluated by detecting the H3-K9me3 levels using Western blot analysis

    Supplementary Fig. S2

    Chaetocin exerts growth inhibition effect on multiple NSCLC cells. Cell lines H1792, A549, H157, H1650, H460 and Calu-1 were incubated with chaetocin at various concentrations (50, 100, 200 nmol/l) for 24 h (a) and 48 h (b), and then cell survival was estimated using SRB assay. Points mean of four replicate determinations; bars S.D. Based on cell viability measurement in (a), IC50 value of chaetocin for tested cell lines was calculated by IBM SPSS Statistics 19 software (c)

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    Liu, X., Guo, S., Liu, X. et al. Chaetocin induces endoplasmic reticulum stress response and leads to death receptor 5-dependent apoptosis in human non-small cell lung cancer cells. Apoptosis 20, 1499–1507 (2015). https://doi.org/10.1007/s10495-015-1167-4

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