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

Area of Science:

• Epigenetics
• Cancer Biology
• Pharmacogenomics

Background:

• Histone deacetylases (HDACs) are key epigenetic regulators in non-small cell lung cancer (NSCLC).
• Responses to HDAC inhibitors (HDACi) differ significantly between lung adenocarcinoma (LUAD) and lung squamous carcinoma (LUSC).

Purpose of the Study:

• To investigate how suberoylanilide hydroxamic acid (SAHA, vorinostat), a pan-HDAC inhibitor, alters lineage-specific transcriptional programs in LUAD and LUSC.
• To determine if SAHA-aligned gene modules, not individual genes, reveal clinically relevant vulnerabilities in each NSCLC subtype.

Main Methods:

• Utilized bulk RNA-sequencing on LUAD-like (NCI-H1299) and LUSC-like (NCI-H1703) cells treated with SAHA or DMSO.
• Performed differential gene expression analysis, gene ontology (GO)/Reactome over-representation, Hallmark Gene Set Enrichment Analysis (GSEA), and protein-protein interaction mapping.
• Constructed SAHA "feature-sensing" modules by intersecting SAHA-responsive differentially expressed genes (DEGs) with overall-survival-associated genes, and analyzed these modules in TCGA LUAD and LUSC tumor cohorts.

Main Results:

• SAHA modulated transcriptomes in both cell lines, inducing shared suppression of cell-cycle programs (E2F/G2-M) but diverging in other outputs.
• In LUAD-like cells, SAHA upregulated morphogenesis/adhesion and KRAS signaling, while dampening interferon/stress pathways, and reduced migration.
• In LUSC-like cells, SAHA triggered cell-cycle checkpoint shutdown, induced complement/ECM and inflammatory responses, increased apoptosis, and showed modest migration restraint. Four SAHA feature-sensing modules were identified, with LUAD_RISK and LUSC_RISK modules stratifying prognosis and linked to distinct HDAC isoform neighborhoods.

Conclusions:

• SAHA establishes a common anti-proliferative effect but activates distinct subtype-specific risk modules in LUAD (cell-cycle/migration-linked) and LUSC (checkpoint/stress-linked).
• These SAHA feature-sensing modules offer a framework for developing subtype-tailored HDAC inhibitor combinations and biomarkers for NSCLC.