Differential Transcriptomic Modulation by Histone Deacetylase Inhibitor SAHA in LUAD and LUSC

Background: Histone deacetylases (HDACs) drive non-small-cell lung cancer (NSCLC) progression, yet HDAC inhibitor (HDACi) responses vary by tumor subtype. We compared the pan-HDAC inhibitor SAHA (vorinostat) in two NSCLC models-HER2-mutant lung adenocarcinoma (NCI-H1299; TP53del, NRASQ61K) and EGFR/PI3K-driven squamous carcinoma (NCI-H1703; PDGFRAamp, PIK3CAE542K)-to uncover lineage-specific mechanisms. Methods: Cells were treated with SAHA (10 µM, 24 h), a clinically relevant dose yielding ~1 µM free drug in plasma. Strand-specific RNA-seq was aligned to GRCh38.p13 and analyzed with edgeR and DESeq2 (FDR < 0.05, |Log₂FC|≥ 1). Pathway, protein-interaction, apoptosis (Annexin V/PI), and migration (scratch, trans-well + mitomycin C) assays complemented transcriptomics. Clinical relevance was assessed by correlating SAHA-regulated genes with disease-free survival in TCGA-LUAD and TCGA-LUSC via GEPIA2. Results: SAHA altered 1098 genes in H1299 and 1532 in H1703, with only 437 shared. In H1299, SAHA induced EMT and MAPK-feedback genes while repressing interferon/apoptosis pathways. In H1703, SAHA activated complement/ECM remodeling and suppressed cell-cycle regulators. Class II HDACs (HDAC4/6) were downregulated only in H1703. Functionally, H1703 exhibited greater apoptosis; H1299 showed stronger migration inhibition. SAHA-reversed gene signatures (e.g., HMMR, PLK1 in LUAD; PAPPA, SAMD11 in LUSC) were significantly associated with poor disease-free survival, defining HDAC9-HMMR/PLK1 and HDAC4/6-PAPPA/SAMD11 axes. Conclusions: SAHA elicits distinct subtype-specific transcriptional and phenotypic effects in NSCLC. These findings highlight the importance of genetic context in HDACi therapy and support tailored combinations-such as SAHA with MAPK inhibitors in LUAD or HDAC4/6-targeted approaches in LUSC-and the use of SAHA-modulated biomarkers for patient stratification.