LncRNA HOTTIP modulated by Hedgehog signaling drives colorectal cancer progression by promoting HUWE1-mediated ubiquitin‒proteasome degradation of p53
Abstract The Hedgehog (Hh) pathway plays critical roles in regulating appropriate tissue morphogenesis and organ formation in the gastrointestinal tract, and its dysregulation has been closely linked to the malignant progression of colorectal cancer. However, the underlying mechanisms are poorly und...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-07-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07817-4 |
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| author | Hui Wang Weiwei Jiao Defu Li Zhengping Yu Huqiao Luo Jie Zhang Yuanbing Zhang Hai Rao Quqin Lu Bing Zhao Shiwen Luo |
| author_facet | Hui Wang Weiwei Jiao Defu Li Zhengping Yu Huqiao Luo Jie Zhang Yuanbing Zhang Hai Rao Quqin Lu Bing Zhao Shiwen Luo |
| author_sort | Hui Wang |
| collection | DOAJ |
| description | Abstract The Hedgehog (Hh) pathway plays critical roles in regulating appropriate tissue morphogenesis and organ formation in the gastrointestinal tract, and its dysregulation has been closely linked to the malignant progression of colorectal cancer. However, the underlying mechanisms are poorly understood. Here, we report that the long noncoding RNA HOXA distal transcript antisense RNA (lncRNA HOTTIP) is a novel Hh target gene and a Hh pathway effector. Activation of Hh signaling induced the expression of the lncRNA HOTTIP. The overexpression of the lncRNA HOTTIP promoted colorectal cancer cell proliferation and tumor growth, whereas HOTTIP knockout exerted the opposite effects in vitro and in vivo. Compared with control mice, AOM/DSS-colorectal cancer model mice with lncRNA Hottip overexpression in Villin-Cre epithelial cells presented notable increases in tumor number and size. Moreover, lncRNA HOTTIP overexpression increased the proliferation and viability of organoids derived from colorectal cancer patients. Mechanistically, the lncRNA HOTTIP binds to HUWE1 and promotes its E3 ubiquitin ligase activity toward p53 and mediating HUWE1-dependent proteasomal turnover of p53, which decreases the level and activity of p53 and results in the overexpression of p53 pathway downstream target genes important for cell proliferation and survival. From a clinical perspective, high levels of the lncRNA HOTTIP were detected in colorectal cancer tissues and were strongly correlated with poor prognosis in colorectal cancer patients. Together, our findings demonstrate that the lncRNA HOTTIP, a novel effector of the Hh pathway, drives colorectal cancer progression by promoting HUWE1-dependent ubiquitin‒proteasome degradation of p53. These findings reveal critical roles of the Hh-HOTTIP-p53 signaling axis in colorectal cancer progression and suggest a potential therapeutic target for colorectal cancer. |
| format | Article |
| id | doaj-art-80a4b1706e3748e7a9f71009fb6ddb8c |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-80a4b1706e3748e7a9f71009fb6ddb8c2025-08-20T04:02:44ZengNature Publishing GroupCell Death and Disease2041-48892025-07-0116111810.1038/s41419-025-07817-4LncRNA HOTTIP modulated by Hedgehog signaling drives colorectal cancer progression by promoting HUWE1-mediated ubiquitin‒proteasome degradation of p53Hui Wang0Weiwei Jiao1Defu Li2Zhengping Yu3Huqiao Luo4Jie Zhang5Yuanbing Zhang6Hai Rao7Quqin Lu8Bing Zhao9Shiwen Luo10Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University; The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors; Jiangxi Medical College, Nanchang UniversityState Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, Institute of Biomedical Sciences, School of Life Sciences, Inner Mongolia UniversityDepartment of Epidemiology and Biostatistics, Jiangxi Provincial Key Laboratory of Disease Prevention and Public Health, School of Public Health, Jiangxi Medical College, Nanchang UniversityCenter for Experimental Medicine, The First Affiliated Hospital of Nanchang University; The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors; Jiangxi Medical College, Nanchang UniversitySchool of Medicine, Shanghai UniversityCenter for Experimental Medicine, The First Affiliated Hospital of Nanchang University; The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors; Jiangxi Medical College, Nanchang UniversityCenter for Experimental Medicine, The First Affiliated Hospital of Nanchang University; The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors; Jiangxi Medical College, Nanchang UniversityDepartment of Biochemistry, School of Medicine, Southern University of Science and TechnologyDepartment of Epidemiology and Biostatistics, Jiangxi Provincial Key Laboratory of Disease Prevention and Public Health, School of Public Health, Jiangxi Medical College, Nanchang UniversityCenter for Experimental Medicine, The First Affiliated Hospital of Nanchang University; The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors; Jiangxi Medical College, Nanchang UniversityCenter for Experimental Medicine, The First Affiliated Hospital of Nanchang University; The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors; Jiangxi Medical College, Nanchang UniversityAbstract The Hedgehog (Hh) pathway plays critical roles in regulating appropriate tissue morphogenesis and organ formation in the gastrointestinal tract, and its dysregulation has been closely linked to the malignant progression of colorectal cancer. However, the underlying mechanisms are poorly understood. Here, we report that the long noncoding RNA HOXA distal transcript antisense RNA (lncRNA HOTTIP) is a novel Hh target gene and a Hh pathway effector. Activation of Hh signaling induced the expression of the lncRNA HOTTIP. The overexpression of the lncRNA HOTTIP promoted colorectal cancer cell proliferation and tumor growth, whereas HOTTIP knockout exerted the opposite effects in vitro and in vivo. Compared with control mice, AOM/DSS-colorectal cancer model mice with lncRNA Hottip overexpression in Villin-Cre epithelial cells presented notable increases in tumor number and size. Moreover, lncRNA HOTTIP overexpression increased the proliferation and viability of organoids derived from colorectal cancer patients. Mechanistically, the lncRNA HOTTIP binds to HUWE1 and promotes its E3 ubiquitin ligase activity toward p53 and mediating HUWE1-dependent proteasomal turnover of p53, which decreases the level and activity of p53 and results in the overexpression of p53 pathway downstream target genes important for cell proliferation and survival. From a clinical perspective, high levels of the lncRNA HOTTIP were detected in colorectal cancer tissues and were strongly correlated with poor prognosis in colorectal cancer patients. Together, our findings demonstrate that the lncRNA HOTTIP, a novel effector of the Hh pathway, drives colorectal cancer progression by promoting HUWE1-dependent ubiquitin‒proteasome degradation of p53. These findings reveal critical roles of the Hh-HOTTIP-p53 signaling axis in colorectal cancer progression and suggest a potential therapeutic target for colorectal cancer.https://doi.org/10.1038/s41419-025-07817-4 |
| spellingShingle | Hui Wang Weiwei Jiao Defu Li Zhengping Yu Huqiao Luo Jie Zhang Yuanbing Zhang Hai Rao Quqin Lu Bing Zhao Shiwen Luo LncRNA HOTTIP modulated by Hedgehog signaling drives colorectal cancer progression by promoting HUWE1-mediated ubiquitin‒proteasome degradation of p53 Cell Death and Disease |
| title | LncRNA HOTTIP modulated by Hedgehog signaling drives colorectal cancer progression by promoting HUWE1-mediated ubiquitin‒proteasome degradation of p53 |
| title_full | LncRNA HOTTIP modulated by Hedgehog signaling drives colorectal cancer progression by promoting HUWE1-mediated ubiquitin‒proteasome degradation of p53 |
| title_fullStr | LncRNA HOTTIP modulated by Hedgehog signaling drives colorectal cancer progression by promoting HUWE1-mediated ubiquitin‒proteasome degradation of p53 |
| title_full_unstemmed | LncRNA HOTTIP modulated by Hedgehog signaling drives colorectal cancer progression by promoting HUWE1-mediated ubiquitin‒proteasome degradation of p53 |
| title_short | LncRNA HOTTIP modulated by Hedgehog signaling drives colorectal cancer progression by promoting HUWE1-mediated ubiquitin‒proteasome degradation of p53 |
| title_sort | lncrna hottip modulated by hedgehog signaling drives colorectal cancer progression by promoting huwe1 mediated ubiquitin proteasome degradation of p53 |
| url | https://doi.org/10.1038/s41419-025-07817-4 |
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