J Korean Med Sci.  2023 Nov;38(45):e381. 10.3346/jkms.2023.38.e381.

Promoter-Specific Variants in NeuroD1 and H3K4me3 Coincident Regions and Clinical Outcomes of Small Cell Lung Cancer

• Yoo SS
• Lee S
• Choi JE
• Hong MJ
• Do SK
• Lee JH
• Lee WK
• Park JE
• Lee YH
• Choi SH
• Seo H
• Lee J
• Lee SY
• Cha SI
• Kim CH
• Kang HG
• Park JY

• KMID: 2547983
• DOI: http://doi.org/10.3346/jkms.2023.38.e381

Abstract

Background
Neurogenic differentiation 1 (NeuroD1) is a representative small cell lung cancer (SCLC) transcription regulator involved in the carcinogenesis and behavior of SCLC. Histone modifications play an important role in transcription, and H3 lysine 4 trimethylation (H3K4me3) is primarily associated with promoter regions.
Methods
We investigated the association between single nucleotide polymorphisms (SNPs) in NeuroD1 and H3K4me3 coincident regions, selected using ChIP sequencing (ChIP-seq), and the clinical outcomes of 261 patients with SCLC.
Results
Among 230 SNPs, two were significantly associated with both the chemotherapy response and overall survival (OS) of patients with SCLC. RNF145 rs2043268A>G was associated with worse chemotherapy response and OS (under a recessive model, adjusted odds ratio [aOR], 0.50, 95% confidence interval [CI], 0.26–0.94, P = 0.031, and adjusted hazard ratio [aHR], 1.88, 95% CI, 1.38–2.57, P < 0.001). CINP rs762105A>G was also associated with worse chemotherapy response and OS (under a dominant model, aOR, 0.47, 95% CI, 0.23–0.99, P = 0.046, and aHR, 2.03, 95% CI, 1.47–2.82, P < 0.001). ChIP–quantitative polymerase chain reaction and luciferase assay confirmed that the two SNPs were located in the active promoter regions and influenced the promoter activity of each gene.
Conclusion
To summarize, among SNPs selected using ChIP-seq in promoter regions with high peaks in both NeuroD1 and H3K4me3, RNF145 rs2043268A>G and CINP rs762105A>G were associated with clinical outcomes in patients with SCLC and also affected the promoter activity of each gene.

Keyword

NeuroD1; H3K4me3; Small Cell Lung Cancer; Variant; ChIP-seq

Figure

• 

  Fig. 1 Kaplan-Meier curves for overall survival according to polymorphisms. RNF145 rs2043268A>G (A, B) and CINP rs762105A>G (C, D). P values were calculated using log-rank (A, C) and multivariate Cox proportional hazards models (B, D).

• 

  Fig. 2 ChIP–quantitative polymerase chain reaction analysis of NeuroD1 and H3K4me3 for RNF145 rs2043268 (A, B) and CINP rs762105 (C, D) in H82 and H524 cancer cell lines. Data are expressed as mean ± standard error of the mean, and P values were calculated using Student’s t-test.NeuroD1 = neurogenic differentiation 1, H3K4me3 = H3 lysine 4 trimethylation.*P < 0.001.

• 

  Fig. 3 Luciferase reporter assays for RNF145 rs2043268A>G (A) and CINP rs762105A>G (B). Data are expressed as mean ± standard error of the mean, and P values were calculated using Student’s t-test.

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