{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRetinoic acid receptor beta (RARB) is a ligand‐activated nuclear receptor that mediates the pleiotropic actions of retinoids on cell differentiation, proliferation, apoptosis, and embryonic organogenesis. In some leukemias, for example, chimeric fusion proteins involving a RAR domain (such as the PML‐RAR fusion) aberrantly recruit epigenetic modifiers to target promoters, thereby enforcing gene silencing and contributing to malignant transformation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In addition, RARB expression is frequently down‐regulated or silenced in a variety of solid tumors—including cervical"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": ", breast"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ", lung"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ", and esophageal cancers"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "—often as a consequence of promoter hypermethylation and altered chromatin structure. Moreover, studies comparing transcriptional activities among RAR isotypes have demonstrated that, unlike RARα, RARB exhibits weak corepressor binding in the absence of ligand and acts as a less repressive but still potent activator upon retinoid binding."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nEpigenetic mechanisms—including DNA hypermethylation, aberrant histone modifications, and microRNA‐mediated repression—frequently contribute to RARB silencing in cancer. In lobular breast carcinomas"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": ", oral premalignant lesions and head and neck squamous cell carcinomas"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": ", and prostate tumors"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": ", RARB (often designated as RARB2 when specifying an isoform) is frequently hypermethylated, with levels of methylation correlating with increased pathological stage and resistance to retinoid‐induced growth inhibition."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": " Similar epigenetic inactivation is observed in papillary thyroid cancers"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": ", acute myeloid leukemia"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": ", and non‐small cell lung cancers."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": " Furthermore, modulation of RARB expression by microRNAs, such as miR‐146 in papillary thyroid carcinoma"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": ", and by dietary methyl donors in breast cancer"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "20"}]}, {"type": "t", "text": ", underscores the importance of epigenetic and post‐transcriptional regulation in dictating RARB tumor suppressor function. Additional studies in cervical"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "and breast cancer"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "21"}]}, {"type": "t", "text": ", as well as in glioblastoma"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "22"}]}, {"type": "t", "text": "and"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "23"}]}, {"type": "t", "text": ", further support the concept that aberrant methylation of the RARB promoter can serve as a diagnostic and prognostic marker.\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its tumor‐suppressive role, RARB participates in complex transcriptional regulatory networks by interacting with other nuclear receptors and coactivators. For instance, cooperation between peroxisome proliferator‐activated receptor gamma ligands and retinoids enhances RARB expression and augments growth‐inhibitory signaling in breast and lung cancer cells."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " RARB also interfaces with molecular chaperones such as HSP70 to directly regulate chromatin structure and facilitate transcriptional activation"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "24"}]}, {"type": "t", "text": ", and its quaternary organization in heterodimeric complexes with RXRα has been elucidated to reveal the structural basis for allosteric signal transmission."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "25"}]}, {"type": "t", "text": " In cell culture models, such as F9 teratocarcinoma cells, RARB target genes govern critical processes such as proliferation and differentiation"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": ", and the unique “gate‐latch” mechanism uncovered in yeast two‐hybrid studies explains the isotype‐specific variances in corepressor binding."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFinally, genetic alterations of RARB—ranging from translocations in acute promyelocytic leukemia"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "26"}]}, {"type": "t", "text": "to de novo missense and truncating mutations that cause syndromic microphthalmia, diaphragmatic hernia, and neurodevelopmental delay"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "27"}]}, {"type": "t", "text": "—demonstrate that both loss‐ and gain‐of‐function alterations of RARB can disrupt retinoid signaling during organogenesis. In the liver, diminished RARB expression in hepatic stellate cells contributes to fibrosis and hepatocellular carcinoma by impairing retinoid‐dependent transcription of cytoskeletal regulators."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "29"}]}, {"type": "t", "text": " Meta‐analyses further corroborate the association between RARB promoter hypermethylation and cancer risk, underscoring its potential as a biomarker."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "30"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Luciano Di Croce, Veronica A Raker, Massimo Corsaro, et al. 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