Ras association domain family member 1 (RASSF1): Molecular characteristics, clinical relevance and therapeutic interventions in cancer

Ras Association Domain Family 1 (RASSF1) proteins are key modulators of tumor suppression, apoptosis, and cell cycle regulation. Among its isoforms, RASSF1A is the most extensively studied due to its crucial role in maintaining cellular homeostasis and preventing cancer progression. It primarily functions as a scaffold protein, orchestrating critical signaling pathways such as Ras, Hippo, and p53 to regulate cell proliferation and apoptosis. Epigenetic silencing of RASSF1A, predominantly through promoter hypermethylation, is a hallmark of numerous human cancers, including those of the lung, breast, and liver. Structural studies have identified conserved domains within RASSF1A, such as the Ras-association (RA) and SARAH domains, which mediate interactions with Ras-GTP and MST kinases to modulate tumor suppressor pathways. Additionally, post-translational modifications (PTMs), such as phosphorylation, influence RASSF1A stability and activity. Dysregulation of RASSF1A impairs several cellular processes, leading to unchecked cell proliferation and tumorigenesis. Understanding the molecular mechanisms regulating RASSF1A—both epigenetically and post-translationally—provides critical insights into potential therapeutic strategies aimed at restoring its tumor-suppressive functions. This review highlights current knowledge of RASSF1A's role in tumorigenesis and explores emerging approaches to target its dysregulation in cancer therapy.