Lactate as a major epigenetic carbon source for histone acetylation via nuclear LDH metabolism
Abstract Histone acetylation involves the transfer of two-carbon units to the nucleus that are embedded in low-concentration metabolites. We found that lactate, a high-concentration metabolic byproduct, can be a major carbon source for histone acetylation through oxidation-dependent metabolism. Both...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-10-01
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| Series: | Experimental and Molecular Medicine |
| Online Access: | https://doi.org/10.1038/s12276-023-01095-w |
| _version_ | 1797637078242033664 |
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| author | Yong Jin An Sihyang Jo Jin-Mo Kim Han Sun Kim Hyun Young Kim Sang-Min Jeon Dawool Han Jong In Yook Keon Wook Kang Sunghyouk Park |
| author_facet | Yong Jin An Sihyang Jo Jin-Mo Kim Han Sun Kim Hyun Young Kim Sang-Min Jeon Dawool Han Jong In Yook Keon Wook Kang Sunghyouk Park |
| author_sort | Yong Jin An |
| collection | DOAJ |
| description | Abstract Histone acetylation involves the transfer of two-carbon units to the nucleus that are embedded in low-concentration metabolites. We found that lactate, a high-concentration metabolic byproduct, can be a major carbon source for histone acetylation through oxidation-dependent metabolism. Both in cells and in purified nuclei, 13C3-lactate carbons are incorporated into histone H4 (maximum incorporation: ~60%). In the purified nucleus, this process depends on nucleus-localized lactate dehydrogenase (LDHA), knockout (KO) of which abrogates incorporation. Heterologous expression of nucleus-localized LDHA reverses the KO effect. Lactate itself increases histone acetylation, whereas inhibition of LDHA reduces acetylation. In vitro and in vivo settings exhibit different lactate incorporation patterns, suggesting an influence on the microenvironment. Higher nuclear LDHA localization is observed in pancreatic cancer than in normal tissues, showing disease relevance. Overall, lactate and nuclear LDHA can be major structural and regulatory players in the metabolism–epigenetics axis controlled by the cell’s own status or the environmental status. |
| first_indexed | 2024-03-11T12:44:14Z |
| format | Article |
| id | doaj.art-e69d02050b8b4d38b7788ff7308d38d4 |
| institution | Directory Open Access Journal |
| issn | 2092-6413 |
| language | English |
| last_indexed | 2024-03-11T12:44:14Z |
| publishDate | 2023-10-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Experimental and Molecular Medicine |
| spelling | doaj.art-e69d02050b8b4d38b7788ff7308d38d42023-11-05T12:08:46ZengNature Publishing GroupExperimental and Molecular Medicine2092-64132023-10-0155102238224710.1038/s12276-023-01095-wLactate as a major epigenetic carbon source for histone acetylation via nuclear LDH metabolismYong Jin An0Sihyang Jo1Jin-Mo Kim2Han Sun Kim3Hyun Young Kim4Sang-Min Jeon5Dawool Han6Jong In Yook7Keon Wook Kang8Sunghyouk Park9Natural Products Research Institute, College of Pharmacy, Seoul National UniversityNatural Products Research Institute, College of Pharmacy, Seoul National UniversityNatural Products Research Institute, College of Pharmacy, Seoul National UniversityNatural Products Research Institute, College of Pharmacy, Seoul National UniversityCollege of Pharmacy, Seoul National UniversityCollege of Pharmacy, Seoul National UniversityDepartment of Oral Pathology, Oral Cancer Research Institute, Yonsei University College of DentistryDepartment of Oral Pathology, Oral Cancer Research Institute, Yonsei University College of DentistryCollege of Pharmacy, Seoul National UniversityNatural Products Research Institute, College of Pharmacy, Seoul National UniversityAbstract Histone acetylation involves the transfer of two-carbon units to the nucleus that are embedded in low-concentration metabolites. We found that lactate, a high-concentration metabolic byproduct, can be a major carbon source for histone acetylation through oxidation-dependent metabolism. Both in cells and in purified nuclei, 13C3-lactate carbons are incorporated into histone H4 (maximum incorporation: ~60%). In the purified nucleus, this process depends on nucleus-localized lactate dehydrogenase (LDHA), knockout (KO) of which abrogates incorporation. Heterologous expression of nucleus-localized LDHA reverses the KO effect. Lactate itself increases histone acetylation, whereas inhibition of LDHA reduces acetylation. In vitro and in vivo settings exhibit different lactate incorporation patterns, suggesting an influence on the microenvironment. Higher nuclear LDHA localization is observed in pancreatic cancer than in normal tissues, showing disease relevance. Overall, lactate and nuclear LDHA can be major structural and regulatory players in the metabolism–epigenetics axis controlled by the cell’s own status or the environmental status.https://doi.org/10.1038/s12276-023-01095-w |
| spellingShingle | Yong Jin An Sihyang Jo Jin-Mo Kim Han Sun Kim Hyun Young Kim Sang-Min Jeon Dawool Han Jong In Yook Keon Wook Kang Sunghyouk Park Lactate as a major epigenetic carbon source for histone acetylation via nuclear LDH metabolism Experimental and Molecular Medicine |
| title | Lactate as a major epigenetic carbon source for histone acetylation via nuclear LDH metabolism |
| title_full | Lactate as a major epigenetic carbon source for histone acetylation via nuclear LDH metabolism |
| title_fullStr | Lactate as a major epigenetic carbon source for histone acetylation via nuclear LDH metabolism |
| title_full_unstemmed | Lactate as a major epigenetic carbon source for histone acetylation via nuclear LDH metabolism |
| title_short | Lactate as a major epigenetic carbon source for histone acetylation via nuclear LDH metabolism |
| title_sort | lactate as a major epigenetic carbon source for histone acetylation via nuclear ldh metabolism |
| url | https://doi.org/10.1038/s12276-023-01095-w |
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