Benzo(a)pyrene disrupts EP300-mediated epigenetic regulation of HSPA1A to alter membrane tension and promote EMT-associated migration and invasion in lung cancer cells.

Benzo(a)pyrene (B(a)P), a prominent environmental carcinogen, is known to promote lung cancer progression; however, its underlying mechanistic pathways remain poorly defined. Here, we identify the EP300-H2BK5ac epigenetic axis as a key regulator of membrane surface tension and epithelial-mesenchymal transition (EMT) in lung cancer cells under B(a)P exposure. Using A549 and SW900 cells, we demonstrate that B(a)P treatment induces a dose-dependent reduction in membrane tension and promotes EMT, migration, and invasion. Mechanistically, B(a)P downregulates EP300 expression, leading to decreased H2BK5ac acetylation and impaired binding of H2BK5ac to the promoter of the endocytosis-related gene HSPA1A, as revealed by co-immunoprecipitation and ChIP-qPCR. EP300 knockdown mimics these effects, enhancing malignant behaviors, whereas EP300 overexpression restores H2BK5ac levels, increases HSPA1A expression, and suppresses B(a)P-induced phenotypes. Notably, HSPA1A overexpression in EP300-deficient cells partially rescues membrane tension and reverses EMT progression. These findings uncover a previously unrecognized EP300-H2BK5ac-HSPA1A regulatory pathway that links environmental exposure to biomechanical and epigenetic remodeling in lung cancer. Targeting this axis may offer new strategies to mitigate B(a)P-driven metastasis.