Defining the heterogeneous molecular landscape of lung cancer cell responses to epigenetic inhibition

Area of Science:

• Cancer Biology
• Epigenetics
• Proteomics

Background:

• Epigenetic inhibitors possess potent antiproliferative and anticancer properties.
• Cellular responses to epigenetic inhibition are highly heterogeneous, influenced by cell genetics, metabolism, and drug specificity.
• Previous studies often examined heterogeneity in single cell lines, limiting comprehensive profiling.

Purpose of the Study:

• To comprehensively profile the effects of small-molecule perturbations on heterogeneous cellular responses.
• To quantify chromatin, proteome, and transcriptome remodeling induced by histone deacetylase inhibitors (HDACi) in non-isogenic cancer cell lines.
• To create a molecular resource for exploring chemical perturbation effects across diverse cell types.

Main Methods:

• Quantitative molecular profiling of 10,621 proteins in HDACi-treated cancer cell lines.
• Analysis of chromatin, proteome, and transcriptome remodeling.
• Development of a web interface for data exploration.

Main Results:

• HDACi treatment induced coordinated molecular remodeling in cancer cells.
• Significant differences in HDACi-regulated proteins were observed across cell lines.
• Identified consistent (JUN, MAP2K3, CDKN1A) and divergent (CCND3, ASF1B, BRD7) cell-state effectors.

Conclusions:

• Cell-type driven and heterogeneous responses are critical considerations for interpreting molecular perturbations in cancer models.
• The generated data resource provides insights into the varied molecular effects of HDAC inhibitors.
• A web interface facilitates exploration of chemical perturbation data in diverse cell types.