{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRASSF1A is a widely studied tumor suppressor that is most notably inactivated through promoter hypermethylation across an array of human cancers. Many investigations have demonstrated that aberrant methylation of the RASSF1A CpG island is an early and tumor‐specific event observed in lung, breast, kidney, pediatric, and even testicular neoplasms. Moreover, its silencing in tumor tissues and even in bodily fluids has promoted interest in its use as a noninvasive biomarker for early cancer detection and prognosis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "21"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its role as a diagnostic marker, RASSF1A functions as a critical mediator of pro‐apoptotic and cell cycle regulatory pathways. Through direct interactions with key kinases such as MST1/2 and the effector LATS1, it disrupts inhibitory complexes (for example, those formed by the Raf1 proto‐oncogene) to promote Bax activation and p73‐mediated transcription of apoptotic genes. RASSF1A thereby links death receptor signaling to mitochondrial apoptosis and regulates p53 stability by facilitating MDM2 self‐ubiquitination."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "22", "end_ref": "32"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nRASSF1A also exerts control over mitotic progression and cytoskeletal dynamics. Its localization on microtubules, centrosomes, and the spindle apparatus enables it to regulate the stability of mitotic cyclins and delay progression through prometaphase by inhibiting APC/Cdc20 activity. Furthermore, interactions with proteins such as PMCA and associations with Rap1 suggest that RASSF1A participates in organizing macromolecular complexes that modulate integrin signaling and microtubule acetylation—processes that ultimately impact tumor cell growth and genomic stability."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "33", "end_ref": "37"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nRecent studies have uncovered additional layers of regulation that fine‐tune RASSF1A function and its tumor suppressive capacity. Regulatory mechanisms now include modulation by long noncoding antisense transcripts that can recruit repressor complexes to the RASSF1A promoter, as well as TGF‐β–induced ubiquitin–proteasome degradation that limits its protein levels. In parallel, transcription factors such as HOXB3 have been implicated in driving DNMT3B expression and subsequent RASSF1A promoter hypermethylation. These novel insights link RASSF1A inactivation not only to cancer initiation but also to enhanced invasive phenotypes and altered therapeutic responsiveness."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "38", "end_ref": "41"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Masayuki Hasegawa, Heather H Nelson, Edward Peters, et al. 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