{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSIX1 is a highly conserved homeodomain‐containing transcription factor that plays a central role during embryogenesis by regulating organogenesis. Its interaction with Eyes Absent (EYA) co‐activators is essential for driving developmental programs in tissues such as the kidney, ear and craniofacial region. In humans, mutations or disruptions of SIX1—as seen in branchio‐oto‐renal and branchio‐otic syndromes—highlight its fundamental role in normal developmental patterning and nephrogenesis, with studies also revealing autoregulatory and cross‐regulatory loops between SIX1 and related factors in nephron progenitor cells."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the context of tumorigenesis, SIX1 is frequently re‐expressed in adult tissues and acts as a potent oncogene. It contributes to malignant transformation by transcriptionally upregulating cell cycle regulators such as cyclin A1 and cyclin D1, thereby promoting cell proliferation in cancers including breast and pancreatic carcinoma. This inappropriate reactivation essentially recapitulates embryonic proliferative signals, driving tumor cell expansion."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond proliferation, aberrantly high levels of SIX1 drive the epithelial‐to‐mesenchymal transition (EMT) and enhance metastatic potential. In various tumor types—including breast, cervical and colorectal cancers—SIX1 shifts transforming growth factor–β (TGF‐β) signaling from tumor suppressive to tumor promotional modes. It represses epithelial markers (for example, E‐cadherin) via direct and indirect mechanisms (such as activating ZEB1 and silencing microRNAs like the miR‐200 family) while inducing pro‐lymphangiogenic factors such as VEGF‐C to foster lymphatic dissemination. Structural and mechanistic studies further indicate that precise SIX1–EYA interactions are critical for these functions, and clinical correlations document that SIX1 overexpression is closely associated with aggressive disease and poor patient prognosis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "24"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nSIX1 also influences tumor metabolism by directly upregulating the expression of a suite of glycolytic genes, thereby reinforcing the Warburg effect to meet the energetic and biosynthetic demands of proliferating cancer cells. Its activity is modulated by post‐translational modifications that enhance protein stability, linking SIX1’s transcriptional output to a metabolic reprogramming that actively supports tumor growth."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "25", "end_ref": "28"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdditional genetic studies have linked SIX1 to the regulation of the optic nerve head and ocular development, with associations to parameters such as optic disc area and vertical cup–disc ratio implicated in glaucoma. This underscores the broad biological impact of SIX1—from its foundational roles in development to its aberrant reactivation in pathological conditions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "29"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Rainer G Ruf, Pin-Xian Xu, Derek Silvius, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Branchiootorenal syndrome and oculoauriculovertebral spectrum features associated with duplication of SIX1, SIX6, and OTX2 resulting from a complex chromosomal rearrangement."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Med Genet A (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ajmg.a.32398"}], "href": "https://doi.org/10.1002/ajmg.a.32398"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18666230"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18666230"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Naoya Morisada, Kandai Nozu, Kazumoto Iijima "}, {"type": "b", "children": [{"type": "t", "text": "Branchio-oto-renal syndrome: comprehensive review based on nationwide surveillance in Japan."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Pediatr Int (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/ped.12357"}], "href": "https://doi.org/10.1111/ped.12357"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24730701"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24730701"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "K T Ng, K Man, C K Sun, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "The miR-106b-25 cluster targets Smad7, activates TGF-β signaling, and induces EMT and tumor initiating cell characteristics downstream of Six1 in human breast cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/onc.2012.11"}], "href": "https://doi.org/10.1038/onc.2012.11"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22286770"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22286770"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Chu-An Wang, Paul Jedlicka, Aaron N Patrick, et al. 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