Lactate Activates the HCAR1/β‐Arrestin2/PP2A Signaling Axis to Mediate STAT1/2 Dephosphorylation and Drive Osteosarcoma Progression
The "Warburg effect", a hallmark of Osteosarcoma(OS), results in lactate accumulation due to aerobic glycolysis. The role and underlying mechanisms of lactate in OS are not well understood. Herein, the lactate-activated hydroxycarboxylate receptor 1(HCAR1) is found to promote OS progression via inhibiting the transcription of anti-oncogene downstream of STAT1/2. The phosphorylation level of STAT1/2 holds considerable significance for transcriptional activity. In this study, protein phosphatase 2A(PP2A) is identified as the tyrosine phosphatase of STAT1/2. Lactate-activated HCAR1, facilitating PP2A interaction with phosphorylated STAT1/2 via β-Arrestin 2, resulting in STAT1/2 dephosphorylation, a key process linked to the aggressive behavior of OS. Using PP2A inhibitor Endothall can abolish the dephosphorylation effect of HCAR1 on STAT1/2, inhibit cancer cell proliferation, migration, and cell cycle, and promote apoptosis. Moreover, the combination of Endothall and Cisplatin is high synergistic in treating OS. In conclusion, the study elucidates the pro-oncogenic role of lactate-activated HCAR1 in OS.
Authors
- Yuanming Chen (ORCID: https://orcid.org/0000-0001-7955-3350)
- Tracy Chenmin Liu
- Feihan F. Dai (ORCID: https://orcid.org/0000-0001-6819-791X)
- Zhitao Han
- Kai Tong (ORCID: https://orcid.org/0000-0002-7279-7114)
- Weina Zhu (ORCID: https://orcid.org/0000-0001-9836-896X)
- Chunlei Zhang (ORCID: https://orcid.org/0000-0002-7781-0218)
- Zhenhua Zhou (ORCID: https://orcid.org/0000-0002-4548-4489)
- Jin Zeng (ORCID: https://orcid.org/0000-0002-0872-587X)
- Xing Huang (ORCID: https://orcid.org/0000-0002-8710-8182)
- Songyi Cheng
- Baoquan Xin
- Guanghui Chen (ORCID: https://orcid.org/0000-0002-1743-138X)
- Jingyu Shen (ORCID: https://orcid.org/0000-0002-4472-5105)
- Jing Zhang (ORCID: https://orcid.org/0000-0002-2488-5021)
- Zhenhua Wang (ORCID: https://orcid.org/0000-0002-7347-8561)
- Qi Jia (ORCID: https://orcid.org/0000-0002-3168-3698)
- Yajie Zhang (ORCID: https://orcid.org/0000-0003-2510-6015)
- Lining Wang (ORCID: https://orcid.org/0000-0001-6173-3361)
- Ting Wang (ORCID: https://orcid.org/0000-0001-5787-4532)
- Li Zhao (ORCID: https://orcid.org/0000-0002-1378-7434)
- Yonggang Liu (ORCID: https://orcid.org/0000-0002-0884-2478)
- Xinghai Yang (ORCID: https://orcid.org/0000-0003-3909-0886)
- Weibo Liu (ORCID: https://orcid.org/0000-0003-3742-8265)
- Yong Ma (ORCID: https://orcid.org/0000-0003-2579-7311)
- Guangjian Bai
- Jiashi Cao (ORCID: https://orcid.org/0000-0001-6980-3424)
Institutions
- Nanjing University of Chinese Medicine (CN)
- Nanchang University (CN)
- University of Shanghai for Science and Technology (CN)
- Guangxi Medical University (CN)
- Second Military Medical University (CN)
- Peking University (CN)
- Chinese PLA General Hospital (CN)
- Shanghai University of Traditional Chinese Medicine (CN)
- Shanghai Changzheng Hospital (CN)
- Traditional Chinese Medicine Hospital of Kunshan (CN)
- Pudong Medical Center (CN)
- Yancheng Third People's Hospital (CN)
- Yancheng Second People's Hospital (CN)
- Peking University Third Hospital (CN)
- First Affiliated Hospital of Nanchang University (CN)
Publication Details
- Journal
- Advanced Science
- Published
- 2025-09-16
- DOI
- https://doi.org/10.1002/advs.202506214
- Citations
- 2
- Primary Topic
- Histone Deacetylase Inhibitors Research
- Type
- article
- Field-Weighted Citation Impact
- 1.61
Funders
- National Natural Science Foundation of China
- Shanghai Rising-Star Program