LDHA-mediated YAP lactylation promotes the tumor progression of hepatocellular carcinoma by inducing YAP dephosphorylation and activation
Abstract Background Hepatocellular carcinoma (HCC) is among the deadliest cancers globally. Yes-Associated Protein (YAP), a Hippo pathway effector, crucially regulates cell proliferation and apoptosis. Recent research has implicated YAP’s role in HCC progression, but the mechanisms are unclear. This...
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| Format: | Article |
| Language: | English |
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BMC
2025-05-01
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| Series: | Biology Direct |
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| Online Access: | https://doi.org/10.1186/s13062-025-00655-6 |
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| author | Xiaoyong Wei Long Zou Yanqing Huang Chuan Qiu Guang Cheng Ye Chen Jun Rao |
| author_facet | Xiaoyong Wei Long Zou Yanqing Huang Chuan Qiu Guang Cheng Ye Chen Jun Rao |
| author_sort | Xiaoyong Wei |
| collection | DOAJ |
| description | Abstract Background Hepatocellular carcinoma (HCC) is among the deadliest cancers globally. Yes-Associated Protein (YAP), a Hippo pathway effector, crucially regulates cell proliferation and apoptosis. Recent research has implicated YAP’s role in HCC progression, but the mechanisms are unclear. This study aims to clarify YAP’s function in HCC, emphasizing its regulation of key pathways and targets. Results Gene knockout and overexpression models were established in nude mice and cell lines of HCC cells to investigate YAP’s impact on tumorigenesis. Additionally, functional assays and molecular biology techniques were employed to identify YAP’s regulatory networks. The study demonstrates that LDHA-regulated lactate production promotes YAP activation and malignant phenotypes in HCC. Overexpression of LDHA in HepG2 and Huh7 cells increased lactate levels and activated the YAP pathway, enhancing cell proliferation, migration, and invasion. Lactate treatment also promoted these malignant phenotypes by inhibiting YAP phosphorylation at Ser127. In a xenograft model, lactate accelerated tumor growth through YAP activation. YAP lactylation at K102 antagonized its Ser127 phosphorylation, further promoting malignant progression. Conclusions This study highlights the significance of YAP in HCC pathogenesis, providing insights into potential therapeutic targets for HCC management. Graphical Abstract |
| format | Article |
| id | doaj-art-fe0e24bd45e64c7087d0f67d55bd60d0 |
| institution | OA Journals |
| issn | 1745-6150 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Biology Direct |
| spelling | doaj-art-fe0e24bd45e64c7087d0f67d55bd60d02025-08-20T01:59:56ZengBMCBiology Direct1745-61502025-05-0120111510.1186/s13062-025-00655-6LDHA-mediated YAP lactylation promotes the tumor progression of hepatocellular carcinoma by inducing YAP dephosphorylation and activationXiaoyong Wei0Long Zou1Yanqing Huang2Chuan Qiu3Guang Cheng4Ye Chen5Jun Rao6Hepatobiliary Surgery, The Second Affiliated Hospital of Nanchang Medical College, Jiangxi Cancer Hospital, Jiangxi Clinical Research Center for CancerHepatobiliary Surgery, The Second Affiliated Hospital of Nanchang Medical College, Jiangxi Cancer Hospital, Jiangxi Clinical Research Center for CancerThe Medical College of Nanchang UniversityThe Medical College of Nanchang UniversityHepatobiliary Surgery, The Second Affiliated Hospital of Nanchang Medical College, Jiangxi Cancer Hospital, Jiangxi Clinical Research Center for CancerHepatobiliary Surgery, The Second Affiliated Hospital of Nanchang Medical College, Jiangxi Cancer Hospital, Jiangxi Clinical Research Center for CancerJiangxi Cancer Hospital, The Second Affiliated Hospital of Nanchang Medical College, Jiangxi Clinical Research Center for CancerAbstract Background Hepatocellular carcinoma (HCC) is among the deadliest cancers globally. Yes-Associated Protein (YAP), a Hippo pathway effector, crucially regulates cell proliferation and apoptosis. Recent research has implicated YAP’s role in HCC progression, but the mechanisms are unclear. This study aims to clarify YAP’s function in HCC, emphasizing its regulation of key pathways and targets. Results Gene knockout and overexpression models were established in nude mice and cell lines of HCC cells to investigate YAP’s impact on tumorigenesis. Additionally, functional assays and molecular biology techniques were employed to identify YAP’s regulatory networks. The study demonstrates that LDHA-regulated lactate production promotes YAP activation and malignant phenotypes in HCC. Overexpression of LDHA in HepG2 and Huh7 cells increased lactate levels and activated the YAP pathway, enhancing cell proliferation, migration, and invasion. Lactate treatment also promoted these malignant phenotypes by inhibiting YAP phosphorylation at Ser127. In a xenograft model, lactate accelerated tumor growth through YAP activation. YAP lactylation at K102 antagonized its Ser127 phosphorylation, further promoting malignant progression. Conclusions This study highlights the significance of YAP in HCC pathogenesis, providing insights into potential therapeutic targets for HCC management. Graphical Abstracthttps://doi.org/10.1186/s13062-025-00655-6HCCYAPLactylationPhosphorylationPoor prognosis |
| spellingShingle | Xiaoyong Wei Long Zou Yanqing Huang Chuan Qiu Guang Cheng Ye Chen Jun Rao LDHA-mediated YAP lactylation promotes the tumor progression of hepatocellular carcinoma by inducing YAP dephosphorylation and activation Biology Direct HCC YAP Lactylation Phosphorylation Poor prognosis |
| title | LDHA-mediated YAP lactylation promotes the tumor progression of hepatocellular carcinoma by inducing YAP dephosphorylation and activation |
| title_full | LDHA-mediated YAP lactylation promotes the tumor progression of hepatocellular carcinoma by inducing YAP dephosphorylation and activation |
| title_fullStr | LDHA-mediated YAP lactylation promotes the tumor progression of hepatocellular carcinoma by inducing YAP dephosphorylation and activation |
| title_full_unstemmed | LDHA-mediated YAP lactylation promotes the tumor progression of hepatocellular carcinoma by inducing YAP dephosphorylation and activation |
| title_short | LDHA-mediated YAP lactylation promotes the tumor progression of hepatocellular carcinoma by inducing YAP dephosphorylation and activation |
| title_sort | ldha mediated yap lactylation promotes the tumor progression of hepatocellular carcinoma by inducing yap dephosphorylation and activation |
| topic | HCC YAP Lactylation Phosphorylation Poor prognosis |
| url | https://doi.org/10.1186/s13062-025-00655-6 |
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