| The Hidden Switch: How RB1 and Epigenetic Mechanisms Turn Lung Cancer Aggressive |
| Paper ID : 1258-IGA |
| Authors |
|
Aria Dehnavi * Aria Dehnavi. Department of Cellular and Molecular Biology, Faculty of Basic Science, Neyshabur Branch, Islamic Azad University, Neyshabur, Iran; Biology Association, Young Researchers and Elite Club, Neyshabur Branch, Islamic Azad University, Neyshabur, Iran |
| Abstract |
| Background and Aim: Small cell lung carcinoma (SCLC) represents one of the most substantial challenges in global health. A subset of lung adenocarcinomas (LUAD) can transdifferentiate into SCLC through epigenetic reprogramming. This study aims to investigate the key epigenetic regulators in this transformation process, and to explore the role of HDAC-YAP signaling in promoting tumor metastasis. Methods: Analysis of scientific databases, clinical studies and reputable articles from 2020 to 2025 identified distinct progression patterns in lung adenocarcinoma: pre-transformation (LUAD-BT) versus non-transforming (LUAD-NT) cases. Data from reviewed articles were analyzed to compare patterns of histone deacetylation, DNA methylation, and transcriptional changes between LUAD-BT and LUAD-NT groups. Special focus was placed on the Rb1-YAP pathway due to its potential role in promoting cancer metastasis. Results: Initial immunohistochemical analysis revealed that unlike other lung cancer subtypes, SCLC tumors lacked Yes-Associated protein (YAP) expression. Molecular studies using ChIP-PCR demonstrated that in Retinoblastoma1(RB1)-deficient cells, E2f transcription factor7 (E2F7) binds to the YAP promoter region. Subsequent experiments confirmed that E2F7 recruits the RCOR-HDAC corepressor complex to mediate epigenetic silencing of YAP. Pharmacological intervention with benzamide-class HDAC inhibitors effectively reversed this silencing and restored YAP expression. In vivo validation studies showed that YAP reconstitution significantly reduced metastatic burden and circulating tumor cell counts. Strikingly, only YAP-negative cells retained full metastatic potential, establishing YAP suppression as a critical driver of SCLC progression. Conclusion: Our work provides new insights into HDAC inhibitors (including vorinostat/SAHA and entinostat/MS-275), reveal their unique inhibitory mechanisms to advance the control of this cancer. |
| Keywords |
| SCLC, Epigenetic, HDAC, YAP- RB1 |
| Status: Accepted |
