{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n HERC4 is a HECT‐domain E3 ubiquitin ligase that functions by catalyzing the polyubiquitination of specific substrate proteins to target them for proteasomal degradation. Its diverse roles have emerged from studies in different biological systems. In the testis, HERC4 is highly expressed during spermiogenesis and is required for the mature spermatozoon to properly shed its cytoplasmic droplet, thereby ensuring optimal motility."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In cancer, HERC4 contributes to disease progression through distinct mechanisms. In multiple myeloma, HERC4 mediates the polyubiquitination of the transcription factor c‐Maf at specific lysine residues, promoting its degradation and impacting cell proliferation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " In breast cancer, overexpression of HERC4 has been correlated with advanced histological grade and TNM stage; mechanistic studies indicate that HERC4 destabilizes the tumor suppressor LATS1, thereby enhancing cell proliferation, survival, and migration."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " Likewise, in hepatocellular carcinoma, HERC4 overexpression is associated with increased proliferative and migratory capacities of tumor cells"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ", and in cervical cancer, HERC4 knockdown leads to reduced levels of Cyclin D1 and Bcl‐2, resulting in decreased proliferation and migration accompanied by enhanced apoptosis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Moreover, modulation of HERC4 activity can have therapeutic implications. Andrographolide treatment in HPV16‐positive cervical cancer cells, for instance, suppresses HERC4 (along with other ubiquitin ligases), thereby restoring p53 levels and triggering apoptosis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " In a broader context, early characterization of the HERC family highlighted HERC4 as a distinct member with potential functional diversity"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": ", and recent reviews support its candidacy as both a biomarker and a therapeutic target in various malignancies."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Clara I Rodriguez, Colin L Stewart "}, {"type": "b", "children": [{"type": "t", "text": "Disruption of the ubiquitin ligase HERC4 causes defects in spermatozoon maturation and impaired fertility."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Dev Biol (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ydbio.2007.09.053"}], "href": "https://doi.org/10.1016/j.ydbio.2007.09.053"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17967448"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17967448"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Zubin Zhang, Jiefei Tong, Xiaowen Tang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The ubiquitin ligase HERC4 mediates c-Maf ubiquitination and delays the growth of multiple myeloma xenografts in nude mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1182/blood-2015-07-658203"}], "href": "https://doi.org/10.1182/blood-2015-07-658203"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26825710"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26825710"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Youqin Xu, Kaiyuan Ji, Meng Wu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A miRNA-HERC4 pathway promotes breast tumorigenesis by inactivating tumor suppressor LATS1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Protein Cell (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s13238-019-0607-2"}], "href": "https://doi.org/10.1007/s13238-019-0607-2"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30710319"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30710319"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Hui Zhou, Rong Shi, Yaowu Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "[Expression of E3 ligase HERC4 in breast cancer and its clinical implications]."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nan Fang Yi Ke Da Xue Xue Bao (2014)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25176076"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25176076"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Yi Zheng, Jie Li, Chenwei Pan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "HERC4 Is Overexpressed in Hepatocellular Carcinoma and Contributes to the Proliferation and Migration of Hepatocellular Carcinoma Cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "DNA Cell Biol (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1089/dna.2016.3626"}], "href": "https://doi.org/10.1089/dna.2016.3626"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28430527"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28430527"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Min Wei, Yan-Ling Zhang, Lan Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "[RNA interference of HERC4 inhibits proliferation, apoptosis and migration of cervical cancer Hela cells]."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nan Fang Yi Ke Da Xue Xue Bao (2016)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28219869"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28219869"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Pariyakorn Udomwan, Chamsai Pientong, Panwad Tongchai, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Proteomics Analysis of Andrographolide-Induced Apoptosis via the Regulation of Tumor Suppressor p53 Proteolysis in Cervical Cancer-Derived Human Papillomavirus 16-Positive Cell Lines."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Mol Sci (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/ijms22136806"}], "href": "https://doi.org/10.3390/ijms22136806"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34202736"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34202736"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Karin Hochrainer, Herbert Mayer, Ulrike Baranyi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The human HERC family of ubiquitin ligases: novel members, genomic organization, expression profiling, and evolutionary aspects."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genomics (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ygeno.2004.10.006"}], "href": "https://doi.org/10.1016/j.ygeno.2004.10.006"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15676274"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15676274"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Xinliang Mao, Gautam Sethi, Zubin Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The Emerging Roles of the HERC Ubiquitin Ligases in Cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Curr Pharm Des (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.2174/1381612824666180528081024"}], "href": "https://doi.org/10.2174/1381612824666180528081024"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29807510"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29807510"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Fang Huang, Xujie Tang, Tao Sun, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SAV1, regulated by HERC4, inhibits the proliferation, migration, and invasion of hepatocellular carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Transl Cancer Res (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.21037/tcr-20-698"}], "href": "https://doi.org/10.21037/tcr-20-698"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35116265"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35116265"}]}]}]}