HACD2 Promotes Pancreatic Cancer Progression by Enhancing PKM2 Dissociation From PRKN in a Dehydratase‐Independent Manner
Abstract 3‐Hydroxyacyl‐CoA dehydratase 2 (HACD2), an obesity‐related gene involved in the elongation of long‐chain fatty acids, is highly expressed in pancreatic cancer (PC) and is associated with patient prognosis. Interestingly, the study reveals that HACD2 mediated the proliferation of PC cells i...
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| Format: | Article |
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Wiley
2025-03-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202407942 |
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| author | Xuanning Chu Jinyu Zhao Yuting Shen Qi Feng Changlin Zhou Lingman Ma Yiran Zhou |
| author_facet | Xuanning Chu Jinyu Zhao Yuting Shen Qi Feng Changlin Zhou Lingman Ma Yiran Zhou |
| author_sort | Xuanning Chu |
| collection | DOAJ |
| description | Abstract 3‐Hydroxyacyl‐CoA dehydratase 2 (HACD2), an obesity‐related gene involved in the elongation of long‐chain fatty acids, is highly expressed in pancreatic cancer (PC) and is associated with patient prognosis. Interestingly, the study reveals that HACD2 mediated the proliferation of PC cells in a dehydratase‐independent manner, affecting the downstream glycolytic pathway. Mechanistically, HACD2 promotes PC cells proliferation by binding to E3 ubiquitin‐protein ligase parkin (PRKN) and enhancing pyruvate kinase PKM (PKM2) dissociation from PRKN, resulting in reduced ubiquitination of PKM2 and increased dimerization of PKM2, which subsequently promote c‐Myc expression and tumor growth. Moreover, HACD2 overexpression‐induced PC growth is mitigated by knockdown of PKM2 or overexpression of PRKN. Furthermore, the weight loss drug orlistat, which potentially binds to HACD2, disrupted the interaction between HACD2 and PRKN and further increased the ubiquitination of PKM2. Therefore, this study elucidates the mechanism by which the obesity‐related gene HACD2 regulates PC cells proliferation through a noncanonical signaling pathway, which may provide a potential new target and strategy for the individualized clinical treatment of PC. |
| format | Article |
| id | doaj-art-04627f08e09e42a4a8ae58ff28662df6 |
| institution | DOAJ |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-04627f08e09e42a4a8ae58ff28662df62025-08-20T03:10:53ZengWileyAdvanced Science2198-38442025-03-011210n/an/a10.1002/advs.202407942HACD2 Promotes Pancreatic Cancer Progression by Enhancing PKM2 Dissociation From PRKN in a Dehydratase‐Independent MannerXuanning Chu0Jinyu Zhao1Yuting Shen2Qi Feng3Changlin Zhou4Lingman Ma5Yiran Zhou6School of Life Science and Technology China Pharmaceutical University Nanjing Jiangsu 211198 ChinaSchool of Life Science and Technology China Pharmaceutical University Nanjing Jiangsu 211198 ChinaSchool of Life Science and Technology China Pharmaceutical University Nanjing Jiangsu 211198 ChinaSchool of Life Science and Technology China Pharmaceutical University Nanjing Jiangsu 211198 ChinaSchool of Life Science and Technology China Pharmaceutical University Nanjing Jiangsu 211198 ChinaSchool of Life Science and Technology China Pharmaceutical University Nanjing Jiangsu 211198 ChinaDepartment of General Surgery Pancreatic Disease Center Ruijin Hospital Shanghai Jiaotong University School of Medicine 197 Ruijin Er Road Shanghai 200025 ChinaAbstract 3‐Hydroxyacyl‐CoA dehydratase 2 (HACD2), an obesity‐related gene involved in the elongation of long‐chain fatty acids, is highly expressed in pancreatic cancer (PC) and is associated with patient prognosis. Interestingly, the study reveals that HACD2 mediated the proliferation of PC cells in a dehydratase‐independent manner, affecting the downstream glycolytic pathway. Mechanistically, HACD2 promotes PC cells proliferation by binding to E3 ubiquitin‐protein ligase parkin (PRKN) and enhancing pyruvate kinase PKM (PKM2) dissociation from PRKN, resulting in reduced ubiquitination of PKM2 and increased dimerization of PKM2, which subsequently promote c‐Myc expression and tumor growth. Moreover, HACD2 overexpression‐induced PC growth is mitigated by knockdown of PKM2 or overexpression of PRKN. Furthermore, the weight loss drug orlistat, which potentially binds to HACD2, disrupted the interaction between HACD2 and PRKN and further increased the ubiquitination of PKM2. Therefore, this study elucidates the mechanism by which the obesity‐related gene HACD2 regulates PC cells proliferation through a noncanonical signaling pathway, which may provide a potential new target and strategy for the individualized clinical treatment of PC.https://doi.org/10.1002/advs.202407942HACD2pancreatic cancerPKM2PRKNubiquitination |
| spellingShingle | Xuanning Chu Jinyu Zhao Yuting Shen Qi Feng Changlin Zhou Lingman Ma Yiran Zhou HACD2 Promotes Pancreatic Cancer Progression by Enhancing PKM2 Dissociation From PRKN in a Dehydratase‐Independent Manner Advanced Science HACD2 pancreatic cancer PKM2 PRKN ubiquitination |
| title | HACD2 Promotes Pancreatic Cancer Progression by Enhancing PKM2 Dissociation From PRKN in a Dehydratase‐Independent Manner |
| title_full | HACD2 Promotes Pancreatic Cancer Progression by Enhancing PKM2 Dissociation From PRKN in a Dehydratase‐Independent Manner |
| title_fullStr | HACD2 Promotes Pancreatic Cancer Progression by Enhancing PKM2 Dissociation From PRKN in a Dehydratase‐Independent Manner |
| title_full_unstemmed | HACD2 Promotes Pancreatic Cancer Progression by Enhancing PKM2 Dissociation From PRKN in a Dehydratase‐Independent Manner |
| title_short | HACD2 Promotes Pancreatic Cancer Progression by Enhancing PKM2 Dissociation From PRKN in a Dehydratase‐Independent Manner |
| title_sort | hacd2 promotes pancreatic cancer progression by enhancing pkm2 dissociation from prkn in a dehydratase independent manner |
| topic | HACD2 pancreatic cancer PKM2 PRKN ubiquitination |
| url | https://doi.org/10.1002/advs.202407942 |
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