{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nThe FOXO6 transcription factor is a member of the forkhead box O family, a group of evolutionarily conserved regulators that integrate diverse signals—from insulin and growth factors to oxidative stress—to modulate cell proliferation, differentiation, metabolism, and apoptosis. Unlike its counterparts, FOXO6 exhibits unique regulatory characteristics in its subcellular localization and posttranslational modifications, and its embryonic expression is prominent in the developing brain, while in the adult it is found in select brain regions. These aspects were initially highlighted by the cloning and characterization of the gene in mice, which underscored its distinct nuclear distribution and regulation compared with other FOXO members"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ";."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFOXO6 plays a key role in metabolic regulation, particularly in the liver. It mediates insulin action on hepatic gluconeogenesis, where its activation in fasting conditions contributes to glucose production, and its aberrant induction is associated with features of type 2 diabetes and obesity. Moreover, FOXO6 is implicated in endoplasmic reticulum stress–induced lipogenesis, and its modulation—such as through isoflurane preconditioning—can protect hepatocytes against oxygen–glucose deprivation by altering downstream signaling via factors like c-Myc and Nrf2"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ";"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ";"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ";."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the context of cancer, FOXO6 exhibits dichotomous roles that appear to be highly context-dependent. In gastric cancer, overexpression of FOXO6 has been linked to enhanced tumor cell proliferation through the induction of oncogenic factors such as C-myc, and its expression positively correlates with invasion markers like MMP-9—findings supported by studies on ceRNA networks involving noncoding RNAs. Similarly, in colorectal cancer cells, elevated FOXO6 promotes cell proliferation, migration, and glycolytic metabolism via activation of the PI3K/Akt/mTOR signaling cascade. In hepatocellular carcinoma, FOXO6 is upregulated downstream of 5-HT1D receptor-mediated stabilization of PIK3R1, thereby contributing to tumor progression, whereas in lung cancer, forced FOXO6 expression induces tumor‐suppressive pathways by increasing USP7 and p53 levels. Furthermore, in nasopharyngeal carcinoma, dysregulated FOXO6—modulated by long noncoding RNAs and microRNAs—fosters malignant progression, and genetic variants in FOXO6 may serve as biomarkers for breast cancer risk, even though no significant association has been observed between FOXO6 polymorphisms and longevity in certain populations"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ";"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": ";"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": ";"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": ";"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": ";"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": ";"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": ";"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": ";."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond metabolism and tumorigenesis, FOXO6 participates in oxidative stress and apoptotic processes. In retinal pigment epithelial cells challenged by high glucose, FOXO6 overexpression exacerbates the production of reactive oxygen species and apoptosis, an effect that can be mitigated by its knockdown through activation of the Akt/Nrf2 pathway. A similar pattern is observed in cardiomyocytes exposed to hypoxic conditions, where FOXO6 knockdown enhances cell viability and reduces oxidative stress via upregulation of SIRT6 and subsequent activation of Nrf2-mediated antioxidant defenses"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": ";."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFinally, emerging evidence suggests a role for FOXO6 in modulating DNA damage repair processes, an insight that may have implications for intervertebral disc degeneration."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": " Taken together, the multifaceted functions of FOXO6 in metabolic regulation, oncogenesis, oxidative stress, and DNA repair underscore its potential as both a biomarker and a therapeutic target across a spectrum of human diseases.\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Frank M J Jacobs, Lars P van der Heide, Patrick J E C Wijchers, et al. "}, {"type": "b", "children": [{"type": "t", "text": "FoxO6, a novel member of the FoxO class of transcription factors with distinct shuttling dynamics."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M302804200"}], "href": "https://doi.org/10.1074/jbc.M302804200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12857750"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12857750"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Guri Tzivion, Melissa Dobson, Gopalakrishnan Ramakrishnan "}, {"type": "b", "children": [{"type": "t", "text": "FoxO transcription factors; Regulation by AKT and 14-3-3 proteins."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochim Biophys Acta (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbamcr.2011.06.002"}], "href": "https://doi.org/10.1016/j.bbamcr.2011.06.002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21708191"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21708191"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Dae Hyun Kim, German Perdomo, Ting Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "FoxO6 integrates insulin signaling with gluconeogenesis in the liver."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Diabetes (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.2337/db11-0548"}], "href": "https://doi.org/10.2337/db11-0548"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21940782"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21940782"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Dae Hyun Kim, Ting Zhang, Sojin Lee, et al. "}, {"type": "b", "children": [{"type": "t", "text": "FoxO6 in glucose metabolism (FoxO6)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Diabetes (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/1753-0407.12027"}], "href": "https://doi.org/10.1111/1753-0407.12027"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23324123"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23324123"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Dae Hyun Kim, Byeong Moo Kim, Ki Wung Chung, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Interaction between CHOP and FoxO6 promotes hepatic lipid accumulation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Liver Int (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/liv.14594"}], "href": "https://doi.org/10.1111/liv.14594"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32639626"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32639626"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Yonghui Zhong, Xuefang Hu, Liangsheng Miao "}, {"type": "b", "children": [{"type": "t", "text": "Isoflurane preconditioning protects hepatocytes from oxygen glucose deprivation injury by regulating FoxO6."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biosci (2019)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31894125"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31894125"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Zhigang Miao, Xiaozhong Guo, Liang Tian "}, {"type": "b", "children": [{"type": "t", "text": "The long noncoding RNA NORAD promotes the growth of gastric cancer cells by sponging miR-608."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Gene (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.gene.2018.11.052"}], "href": "https://doi.org/10.1016/j.gene.2018.11.052"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30453063"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30453063"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Quanying Li, Hongna Tang, Fangfang Hu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Silencing of FOXO6 inhibits the proliferation, invasion, and glycolysis in colorectal cancer cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Biochem (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/jcb.27667"}], "href": "https://doi.org/10.1002/jcb.27667"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30321450"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30321450"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Xueliang Zuo, Zhiqiang Chen, Juan Cai, et al. "}, {"type": "b", "children": [{"type": "t", "text": "5-Hydroxytryptamine Receptor 1D Aggravates Hepatocellular Carcinoma Progression Through FoxO6 in AKT-Dependent and Independent Manners."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hepatology (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/hep.30430"}], "href": "https://doi.org/10.1002/hep.30430"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30561038"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30561038"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Hong-Jun Hu, Li-Guo Zhang, Zhen-Hua Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "FoxO6 inhibits cell proliferation in lung carcinoma through up-regulation of USP7."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Med Rep (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3892/mmr.2015.3362"}], "href": "https://doi.org/10.3892/mmr.2015.3362"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25695151"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25695151"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Jia-Hong Wang, Hong-Sheng Tang, Xiao-Shan Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Elevated FOXO6 expression correlates with progression and prognosis in gastric cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncotarget (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.18632/oncotarget.15920"}], "href": "https://doi.org/10.18632/oncotarget.15920"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28404958"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28404958"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Haijiao Wang, Hongliang Liu, Lingling Zhao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Association of genetic variants of FBXO32 and FOXO6 in the FOXO pathway with breast cancer risk."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Carcinog (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/mc.23331"}], "href": "https://doi.org/10.1002/mc.23331"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34197655"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34197655"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Zhiyuan Tang, Xianhai Zeng, Juanjuan Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "LncRNA HOXC-AS1 promotes nasopharyngeal carcinoma (NPC) progression by sponging miR-4651 and subsequently upregulating FOXO6."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Pharmacol Sci (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jphs.2021.08.002"}], "href": "https://doi.org/10.1016/j.jphs.2021.08.002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34507637"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34507637"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Rabea Kleindorp, Friederike Flachsbart, Annibale A Puca, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Candidate gene study of FOXO1, FOXO4, and FOXO6 reveals no association with human longevity in Germans."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Aging Cell (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1474-9726.2011.00698.x"}], "href": "https://doi.org/10.1111/j.1474-9726.2011.00698.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21388494"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21388494"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Zhuolin Zhou, Jing Liu, Chunchao Bi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Knockdown of FOXO6 inhibits high glucose-induced oxidative stress and apoptosis in retinal pigment epithelial cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Biochem (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/jcb.28252"}], "href": "https://doi.org/10.1002/jcb.28252"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30548643"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30548643"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Aiping Jin, Qianrong Zhang, Shulin Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Downregulation of FOXO6 alleviates hypoxia-induced apoptosis and oxidative stress in cardiomyocytes by enhancing Nrf2 activation via upregulation of SIRT6."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Bioenerg Biomembr (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s10863-020-09856-2"}], "href": "https://doi.org/10.1007/s10863-020-09856-2"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33123950"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33123950"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "L Cong, X-L Zhang, X-K Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Upregulation of FoxO6 in nucleus pulposus cells promotes DNA damage repair via activation of RAD51."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur Rev Med Pharmacol Sci (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.26355/eurrev_202109_26646"}], "href": "https://doi.org/10.26355/eurrev_202109_26646"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34533813"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34533813"}]}]}]}