IGF2BP3/ESM1/KLF10/BECN1 positive feedback loop: a novel therapeutic target in ovarian cancer via lipid metabolism reprogramming
Abstract Ovarian cancer (OC) is often detected at an advanced stage and has a high recurrence rate after surgery or chemotherapy. Thus, it is essential to develop new strategies for OC treatment. This study tended to investigate the effects of endothelial cell-specific molecule 1 (ESM1) in OC. The i...
Saved in:
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2025-04-01
|
| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07571-7 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850148879580790784 |
|---|---|
| author | Anbo Gao Juan Zou Tian Zeng Mei Qin Xing Tang Ting Yi Guangming Song Jie Zhong Yuhuan Zeng Wenchao Zhou Qin Gao Qunfeng Zhang Juan Zhang Yukun Li |
| author_facet | Anbo Gao Juan Zou Tian Zeng Mei Qin Xing Tang Ting Yi Guangming Song Jie Zhong Yuhuan Zeng Wenchao Zhou Qin Gao Qunfeng Zhang Juan Zhang Yukun Li |
| author_sort | Anbo Gao |
| collection | DOAJ |
| description | Abstract Ovarian cancer (OC) is often detected at an advanced stage and has a high recurrence rate after surgery or chemotherapy. Thus, it is essential to develop new strategies for OC treatment. This study tended to investigate the effects of endothelial cell-specific molecule 1 (ESM1) in OC. The impact of ESM1 on lipid metabolism was investigated through the regulation of ESM1 expression. Differential genes regulated by ESM1 were screened by mRNA sequencing. The role of autophagy in ESM1 regulation on lipid metabolism was explored using autophagy inhibitor chloroquine (CQ). Co-IP, dual-luciferase reporter assay, actinomycin D treatment assay, and others were used to analyze the mechanism of ESM1 regulation on lipid metabolism. The xenograft mouse model was constructed to explore the impact of ESM1 regulation on OC development. The regulatory mechanism of ESM1 in OC patient samples was verified by using microarray analysis and the Log-rank (Mantel-Cox) test. After ESM1 silencing, cholesterol synthesis decreased and lipolysis increased. mRNA sequencing revealed that ESM1 regulation on lipid metabolism was related to Beclin 1 (BECN1). In vitro experiments, ESM1 inhibited lipolysis by suppressing BECN1-mediated autophagy. BECN1 expression was regulated by the transcription factor Kruppel-like factor 10 (KLF10). The competitive binding between BECN1 and HSPA5 promoted the ubiquitination degradation of HMGCR, thereby inhibiting cholesterol production. The intervention experiment with exogenous cholesterol showed a positive correlation between m6A reader IGF2BP3 expression and cholesterol content. Mechanistically, IGF2BP3 regulated the stability of ESM1 mRNA. In vivo experiments, ESM1 modified by m6A methylation promoted cholesterol synthesis and inhibited lipolysis. High expression of ESM1 predicted poor prognosis in OC patients. ESM1 regulated lipid metabolism through IGF2BP3/ESM1/KLF10/BECN1 positive feedback, which was a promising target for OC treatment. |
| format | Article |
| id | doaj-art-899ceb7d8def4dbebf02a94d654f9faf |
| institution | OA Journals |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-899ceb7d8def4dbebf02a94d654f9faf2025-08-20T02:27:06ZengNature Publishing GroupCell Death and Disease2041-48892025-04-0116111410.1038/s41419-025-07571-7IGF2BP3/ESM1/KLF10/BECN1 positive feedback loop: a novel therapeutic target in ovarian cancer via lipid metabolism reprogrammingAnbo Gao0Juan Zou1Tian Zeng2Mei Qin3Xing Tang4Ting Yi5Guangming Song6Jie Zhong7Yuhuan Zeng8Wenchao Zhou9Qin Gao10Qunfeng Zhang11Juan Zhang12Yukun Li13Clinical Research Institute, The Second Affiliated Hospital, University of South ChinaHengyang Medical School, University of South ChinaHengyang Medical School, University of South ChinaDepartment of Gynecology, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South UniversityDepartment of Assisted Reproductive Centre, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South UniversityDepartment of Trauma Center, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South UniversityHengyang Medical School, University of South ChinaHengyang Medical School, University of South ChinaHengyang Medical School, University of South ChinaHengyang Medical School, University of South ChinaHengyang Medical School, University of South ChinaHengyang Medical School, University of South ChinaDepartment of Assisted Reproductive Centre, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South UniversityHengyang Medical School, University of South ChinaAbstract Ovarian cancer (OC) is often detected at an advanced stage and has a high recurrence rate after surgery or chemotherapy. Thus, it is essential to develop new strategies for OC treatment. This study tended to investigate the effects of endothelial cell-specific molecule 1 (ESM1) in OC. The impact of ESM1 on lipid metabolism was investigated through the regulation of ESM1 expression. Differential genes regulated by ESM1 were screened by mRNA sequencing. The role of autophagy in ESM1 regulation on lipid metabolism was explored using autophagy inhibitor chloroquine (CQ). Co-IP, dual-luciferase reporter assay, actinomycin D treatment assay, and others were used to analyze the mechanism of ESM1 regulation on lipid metabolism. The xenograft mouse model was constructed to explore the impact of ESM1 regulation on OC development. The regulatory mechanism of ESM1 in OC patient samples was verified by using microarray analysis and the Log-rank (Mantel-Cox) test. After ESM1 silencing, cholesterol synthesis decreased and lipolysis increased. mRNA sequencing revealed that ESM1 regulation on lipid metabolism was related to Beclin 1 (BECN1). In vitro experiments, ESM1 inhibited lipolysis by suppressing BECN1-mediated autophagy. BECN1 expression was regulated by the transcription factor Kruppel-like factor 10 (KLF10). The competitive binding between BECN1 and HSPA5 promoted the ubiquitination degradation of HMGCR, thereby inhibiting cholesterol production. The intervention experiment with exogenous cholesterol showed a positive correlation between m6A reader IGF2BP3 expression and cholesterol content. Mechanistically, IGF2BP3 regulated the stability of ESM1 mRNA. In vivo experiments, ESM1 modified by m6A methylation promoted cholesterol synthesis and inhibited lipolysis. High expression of ESM1 predicted poor prognosis in OC patients. ESM1 regulated lipid metabolism through IGF2BP3/ESM1/KLF10/BECN1 positive feedback, which was a promising target for OC treatment.https://doi.org/10.1038/s41419-025-07571-7 |
| spellingShingle | Anbo Gao Juan Zou Tian Zeng Mei Qin Xing Tang Ting Yi Guangming Song Jie Zhong Yuhuan Zeng Wenchao Zhou Qin Gao Qunfeng Zhang Juan Zhang Yukun Li IGF2BP3/ESM1/KLF10/BECN1 positive feedback loop: a novel therapeutic target in ovarian cancer via lipid metabolism reprogramming Cell Death and Disease |
| title | IGF2BP3/ESM1/KLF10/BECN1 positive feedback loop: a novel therapeutic target in ovarian cancer via lipid metabolism reprogramming |
| title_full | IGF2BP3/ESM1/KLF10/BECN1 positive feedback loop: a novel therapeutic target in ovarian cancer via lipid metabolism reprogramming |
| title_fullStr | IGF2BP3/ESM1/KLF10/BECN1 positive feedback loop: a novel therapeutic target in ovarian cancer via lipid metabolism reprogramming |
| title_full_unstemmed | IGF2BP3/ESM1/KLF10/BECN1 positive feedback loop: a novel therapeutic target in ovarian cancer via lipid metabolism reprogramming |
| title_short | IGF2BP3/ESM1/KLF10/BECN1 positive feedback loop: a novel therapeutic target in ovarian cancer via lipid metabolism reprogramming |
| title_sort | igf2bp3 esm1 klf10 becn1 positive feedback loop a novel therapeutic target in ovarian cancer via lipid metabolism reprogramming |
| url | https://doi.org/10.1038/s41419-025-07571-7 |
| work_keys_str_mv | AT anbogao igf2bp3esm1klf10becn1positivefeedbackloopanoveltherapeutictargetinovariancancervialipidmetabolismreprogramming AT juanzou igf2bp3esm1klf10becn1positivefeedbackloopanoveltherapeutictargetinovariancancervialipidmetabolismreprogramming AT tianzeng igf2bp3esm1klf10becn1positivefeedbackloopanoveltherapeutictargetinovariancancervialipidmetabolismreprogramming AT meiqin igf2bp3esm1klf10becn1positivefeedbackloopanoveltherapeutictargetinovariancancervialipidmetabolismreprogramming AT xingtang igf2bp3esm1klf10becn1positivefeedbackloopanoveltherapeutictargetinovariancancervialipidmetabolismreprogramming AT tingyi igf2bp3esm1klf10becn1positivefeedbackloopanoveltherapeutictargetinovariancancervialipidmetabolismreprogramming AT guangmingsong igf2bp3esm1klf10becn1positivefeedbackloopanoveltherapeutictargetinovariancancervialipidmetabolismreprogramming AT jiezhong igf2bp3esm1klf10becn1positivefeedbackloopanoveltherapeutictargetinovariancancervialipidmetabolismreprogramming AT yuhuanzeng igf2bp3esm1klf10becn1positivefeedbackloopanoveltherapeutictargetinovariancancervialipidmetabolismreprogramming AT wenchaozhou igf2bp3esm1klf10becn1positivefeedbackloopanoveltherapeutictargetinovariancancervialipidmetabolismreprogramming AT qingao igf2bp3esm1klf10becn1positivefeedbackloopanoveltherapeutictargetinovariancancervialipidmetabolismreprogramming AT qunfengzhang igf2bp3esm1klf10becn1positivefeedbackloopanoveltherapeutictargetinovariancancervialipidmetabolismreprogramming AT juanzhang igf2bp3esm1klf10becn1positivefeedbackloopanoveltherapeutictargetinovariancancervialipidmetabolismreprogramming AT yukunli igf2bp3esm1klf10becn1positivefeedbackloopanoveltherapeutictargetinovariancancervialipidmetabolismreprogramming |