HDAC1-modified lamin A/C drives nuclear deformation in RB1-deficient lung adenocarcinoma.

Lineage transformation from lung adenocarcinoma (LUAD) to small cell lung cancer (SCLC) represents a rare yet well-documented off-target mechanism associated with acquired resistance to tyrosine kinase inhibitors (TKIs). However, the relationship between this transformation and morphological changes remains inadequately understood. This study seeks to elucidate the molecular mechanisms by which RB1 depletion facilitates lineage transformation, with a particular emphasis on its role in morphological alterations. Integrated molecular, morphological, and structural analyses were conducted in RB1-deficient LUAD models in vitro and in vivo. Functional perturbation and pharmacological inhibition of RB1-associated regulators were further performed to delineate the mechanism of the RB1/E2F1/HDAC1 axis. Patients with LUAD exhibiting low expression levels of TP53 and RB1 exhibited enhanced tumor invasion characteristics and a poor clinical prognosis. Our findings demonstrated that RB1 depletion induced epithelial-mesenchymal transition (EMT) characteristics in LUAD cells, as evidenced by spindle-shaped morphology, increased vimentin expression, and decreased E-cadherin expression. Furthermore, RB1 loss is responsible for nuclear abnormalities, including irregular distribution of nuclear hallmarks such as lamin A/C and emerin, which contribute to tumor aggressiveness. Through the downregulation of individual components of the RB1/E2F1/HDAC1 complex, we identified HDAC1 as a key regulatory factor influencing lamin A/C modification and nuclear deformation. Pharmacological inhibition of HDAC1 derivatives ameliorates the nuclear abnormalities observed in RB1-depleted lung cancer cells, suggesting a potential therapeutic strategy. Mechanistically, the loss of acetylated lamin A/C leads to its degradation and granular distribution, resulting in compromised nuclear mechanostability and defective cytoskeletal dynamics, which may elucidate the observed EMT. Collectively, our findings suggested that the downregulation of RB1 significantly influences the morphology of LUAD by facilitating EMT and nuclear abnormalities through HDAC1-mediated deacetylation of lamin A/C. Future research should prioritize the development of targeted therapies aimed at restoring RB1 function or inhibiting HDAC1 to mitigate cancer progression, thereby enhancing patient stratification and treatment strategies in TKI-resistant LUAD.