BRG1 is one of two catalytic subunits of the SWI/SNF ATP-dependent chromatin-remodeling complex. In cancer, it has been hypothesized that BRG1 acts as a tumor suppressor. Further study has shown that, under certain circumstances, BRG1 acts as an oncogene. Targeted knockout of BRG1 has proven successful in most cancers in suppressing tumor growth and proliferation. Furthermore, BRG1 effects cancer proliferation in oncogenic KRAS mutated cancers, with varying directionality. Thus, dissecting BRG1’s interaction with various cellular pathways can highlight possible intermediates that can facilitate the design of different treatment methods, including BRG1 inhibition. Autophagy and apoptosis are two important cellular responses to stress. BRG1 plays a direct role in autophagy and apoptosis and likely promotes autophagy and suppresses apoptosis, supporting unfettered cancer growth. PRMT5 inhibits transcription by interacting with ATP-dependent chromatin remodeling complexes, such as SWI/SNF. When PRMT5 associates with the SWI/SNF complex, including BRG1, it represses tumor suppressor genes. The Ras/Raf/MAPK/ERK1/2 pathway in cancers is a signal transduction pathway involved in the transcription of genes related to cancer survival. BRG1 has been shown to effect KRAS-driven cancer growth. BRG1 associates with several proteins within the signal transduction pathway. In this review, we analyze BRG1 as a promising target for cancer inhibition and possible synergy with other cancer treatments.
Introduction: Therapeutic approaches to target mutant KRAS is in progress, and transcription regulator PRMT5 (Protein arginine methyltransferase) has been previously reported to be a viable, surrogate target. Mutation of oncogenic KRAS is prevalent in several cancer types often rendering aggressiveness to the disease. Herein we used extensive molecular dynamics simulations to understand the intermediate complexities of the cross-talk. Methodology: GROMACS is a Molecular Dynamics Simulation software that renders a topology regulated by Newton’s Laws that can be employed to simulate interactions between proteins. Utilizing the STRING database, multiple pathways from KRAS linked to PRMT5 were extrapolated. Confidence values were determined. Protein complexes were downloaded from RCSB archives. Protein pairs were submitted to HDOCK for docking. Proteins were separated by chain identities, using PYMOL. Proteins were solvated and paired in GROMACS, and charges were neutralized. Each complex underwent energy minimization to configure the proteins in the most energetically favorable conformation. The complex was equilibrated and simulated. XmGrace was used to graph radius gyration between both proteins and their stabilities. The data produced were used to analyze the favorable interaction of the various pathways. Results: Three pathways were analyzed, with high, intermediate, and low confidence values of interaction. The intermediate mediators were simulated in pairs and energy scoring was performed for each interaction. The radius of gyration (Rg) values was calculated for each protein in its respective pathway. A cutoff of 10 nanoseconds was used to confirm stability. A scale was constructed to predict the order of operations of each pathway. HRAS was determined to be actively involved in the crosstalk. Conclusion: The crosstalk between PRMT5 and KRAS can be achieved through three different biochemical pathways with varying levels of confidence. Potentially, if one pathway is affected, an alternative route could be activated to achieve signaling toward PRMT5. These pathways introduce a more targeted approach toward discovering therapeutic advances against KRAS. More simulations are underway to compare the interactions of wildtype and mutant KRAS with their respective pathway intermediates. Citation Format: Isaac V. Silverman, Yitzchak F. Stein, Michael Shawn Gerber, Radhashree Maitra, Sanjay Goel. Molecular dynamic simulation of intermediates connecting KRAS and PRMT5 insight for targeting KRAS [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2040.
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