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Background <p>Histone deacetylases (HDACs) are central epigenetic regulators in non-small cell lung cancer (NSCLC), yet responses to HDAC inhibitors (HDACi) vary markedly between lung adenocarcinoma (LUAD) and lung squamous carcinoma (LUSC). We asked how the pan-HDAC inhibitor suberoylanilide hydroxamic acid (SAHA, vorinostat) rewires lineage-specific transcriptional programs and whether SAHA-aligned <i>modules</i> of genes, rather than individual loci, capture clinically relevant vulnerabilities in each subtype.</p> Methods <p>LUAD-like NCI-H1299 (TP53<sup>del</sup>, NRAS<sup>Q61K</sup>) and LUSC-like NCI-H1703 (TP53<sup>WT</sup>, PDGFRA<sup>amp</sup>, PIK3CA<sup>E542K</sup>) cells were treated with SAHA (10&#xa0;µM, 24&#xa0;h) or DMSO. Bulk RNA-seq data were analysed with edgeR (FDR &lt; 0.05, |log<sub>2</sub>FC|&gt; 1), followed by GO/Reactome over-representation, Hallmark GSEA, and STRING-based protein–protein interaction mapping. We quantified apoptosis (Annexin V/PI) and motility (scratch assays under mitomycin C). SAHA “feature-sensing” modules were constructed by intersecting SAHA-responsive DEGs with overall-survival–associated genes from GEPIA2 and were scored in 592 LUAD and 551 LUSC tumours. Correlations between HDAC isoforms and module scores were used to define subtype-biased HDAC–module neighbourhoods.</p> Results <p>SAHA reprogrammed the transcriptome in both lines (1,098 DEGs in H1299; 1,532 in H1703), enforcing a shared suppression of E2F/G2–M programs but diverging in non-cell-cycle outputs. In LUAD-like H1299, SAHA upregulated morphogenesis/adhesion and KRAS_SIGNALING_DN/EMT-adjacent signatures while dampening interferon/stress pathways, and significantly reduced migration at low dose. In LUSC-like H1703, SAHA triggered a dominant cell-cycle checkpoint shutdown coupled to complement/ECM and inflammatory induction, with stronger apoptosis but only modest short-term migration restraint. Survival-anchored analysis yielded four SAHA feature-sensing modules; the LUAD_RISK module was enriched for cell-cycle/mitotic genes and was attenuated by SAHA, whereas the LUSC_RISK module captured checkpoint, ECM, and stress-response programs preferentially down-regulated in H1703. Both risk modules stratified prognosis and were linked to distinct HDAC-centred neighbourhoods (HDAC7/9–LUAD_RISK and HDAC4/6–LUSC_RISK) in TCGA tumours.</p> Conclusions <p>SAHA imposes a common anti-proliferative core but engages distinct lineage-conditioned risk modules in LUAD and LUSC—cell-cycle/migration-linked in LUAD and checkpoint/stress-linked in LUSC. These SAHA feature-sensing modules provide a mechanistic and clinically anchored framework for subtype-tailored HDAC-directed combinations and for future development of HDACi-aligned biomarkers in NSCLC.</p>

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Differential transcriptomic modulation by histone deacetylase inhibitor SAHA in LUAD and LUSC

  • 期刊论文

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  • 发表日期：

    2026年1月27日

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  • Fei Wang,
  • Qingjun Yang,
  • Lei Shu,
  • Huiyu Cen,
  • Yating Huang,
  • Xiaojun Ma,
  • Yinshan Lin,
  • Xiaoling Guan,
  • Chen Wang,
  • Xihua Fu,
  • Guoxing You,
  • Xi-Yong Yu,
  • Lingmin Zhang,
  • Jianfen Su

摘要

Background

Histone deacetylases (HDACs) are central epigenetic regulators in non-small cell lung cancer (NSCLC), yet responses to HDAC inhibitors (HDACi) vary markedly between lung adenocarcinoma (LUAD) and lung squamous carcinoma (LUSC). We asked how the pan-HDAC inhibitor suberoylanilide hydroxamic acid (SAHA, vorinostat) rewires lineage-specific transcriptional programs and whether SAHA-aligned modules of genes, rather than individual loci, capture clinically relevant vulnerabilities in each subtype.

Methods

LUAD-like NCI-H1299 (TP53del, NRASQ61K) and LUSC-like NCI-H1703 (TP53WT, PDGFRAamp, PIK3CAE542K) cells were treated with SAHA (10 µM, 24 h) or DMSO. Bulk RNA-seq data were analysed with edgeR (FDR < 0.05, |log2FC|> 1), followed by GO/Reactome over-representation, Hallmark GSEA, and STRING-based protein–protein interaction mapping. We quantified apoptosis (Annexin V/PI) and motility (scratch assays under mitomycin C). SAHA “feature-sensing” modules were constructed by intersecting SAHA-responsive DEGs with overall-survival–associated genes from GEPIA2 and were scored in 592 LUAD and 551 LUSC tumours. Correlations between HDAC isoforms and module scores were used to define subtype-biased HDAC–module neighbourhoods.

Results

SAHA reprogrammed the transcriptome in both lines (1,098 DEGs in H1299; 1,532 in H1703), enforcing a shared suppression of E2F/G2–M programs but diverging in non-cell-cycle outputs. In LUAD-like H1299, SAHA upregulated morphogenesis/adhesion and KRAS_SIGNALING_DN/EMT-adjacent signatures while dampening interferon/stress pathways, and significantly reduced migration at low dose. In LUSC-like H1703, SAHA triggered a dominant cell-cycle checkpoint shutdown coupled to complement/ECM and inflammatory induction, with stronger apoptosis but only modest short-term migration restraint. Survival-anchored analysis yielded four SAHA feature-sensing modules; the LUAD_RISK module was enriched for cell-cycle/mitotic genes and was attenuated by SAHA, whereas the LUSC_RISK module captured checkpoint, ECM, and stress-response programs preferentially down-regulated in H1703. Both risk modules stratified prognosis and were linked to distinct HDAC-centred neighbourhoods (HDAC7/9–LUAD_RISK and HDAC4/6–LUSC_RISK) in TCGA tumours.

Conclusions

SAHA imposes a common anti-proliferative core but engages distinct lineage-conditioned risk modules in LUAD and LUSC—cell-cycle/migration-linked in LUAD and checkpoint/stress-linked in LUSC. These SAHA feature-sensing modules provide a mechanistic and clinically anchored framework for subtype-tailored HDAC-directed combinations and for future development of HDACi-aligned biomarkers in NSCLC.