Inhibition of ELF3 confers synthetic lethality of PARP inhibitor in non-small cell lung cancer

Abstract

Background

E74 Like ETS Transcription Factor 3 (ELF3) functions as a transcriptional factor to regulate non-small cell lung cancer (NSCLC) differentiation and progression. Poly(ADP-ribose) polymerase (PARP) inhibitors demonstrate anti-tumor effect in NSCLC. This study aimed to investigate whether ELF3 confers synthetic lethal with PARP inhibitor in NSCLC.

Materials and methods

The sensitivity of PARP inhibitor, Olaparib, to different NSCLC cell lines was determined by half maximal inhibitory concentration (IC₅₀). Expression of ELF3 in NSCLC cell lines was evaluated by western blot. The effects of ELF3 on cytotoxicity of Olaparib to NSCLC were investigated by MTT (3-(4,5- di methyl thiazol −2-yl)-2,5-di phenyl tetrazolium bromide) and colony formation assays. The underlying mechanism involved in synthetic lethality with ELF3 and PARP inhibitors in NSCLC were detected by immunofluorescence and Western blot.

Results

ELF3 was up-regulated in NSCLC cell lines exhibiting resistance to PARP inhibitor, Olaparib. Knock down of ELF3 decreased the sensitivity and enhanced cytotoxicity of Olaparib to NSCLC cells. Moreover, knock down of ELF3 increased S139 phosphorylated histone H2AX (γH2AX), and inhibited homologous recombination activity via down-regulation of DNA repair protein RAD51 homolog 1 (RAD51), thus showing deficiency in DNA damage repair. Over-expression of ELF3 could up-regulate phosphorylation of AKT (Protein kinase B), while knock down of ELF3 regulated homologous recombination-mediated DNA repair via down-regulation of phosphorylation of AKT.

Conclusion

Knock down of ELF3 revealed homologous recombination deficiency via AKT signaling pathway, and synthetic lethality with ELF3 inhibition and PARP inhibitor indicated the clinical significance of PARP inhibitor in ELF3-deficient NSCLC.

Keywords:

• ELF3
• PARP
• synthetic lethal
• sensitivity
• AKT

Author contributions

YW and ZQC conceived and designed the experiments, MZ and HTJ analyzed and interpreted the results of the experiments, MNL and JFL performed the experiments.

Disclosure statement

The authors state that there are no conflicts of interest to disclose.

Availability of data and materials

All data generated or analyzed during this study are included in this published article.

Additional information

Funding

This work was supported by the Research Backbone Training Project of Shenzhen People's Hospital Young and Middle-aged People (Grant No. Sykypy201901).