Nuclear-localized HKDC1 promotes hepatocellular carcinoma through phosphorylating RBBP5 to upregulate H3K4me3
Summary: Metabolic enzymes play significant roles in the pathogenesis of various cancers through both canonical and noncanonical functions. Hexokinase domain-containing protein 1 (HKDC1) functions beyond glucose metabolism, but its underlying mechanisms in tumorigenesis are not fully understood. Her...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-02-01
|
| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S221112472500021X |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832573222487326720 |
|---|---|
| author | Ling Ye Shengqi Shen Qiankun Mao Hui Lu Haiying Liu Pinggen Zhang Zetan Jiang Wenhao Ma Yuchen Sun Yiyang Chu Zilong Zhou Rui Liu Jian Li Shi-ting Li Ping Gao Huafeng Zhang |
| author_facet | Ling Ye Shengqi Shen Qiankun Mao Hui Lu Haiying Liu Pinggen Zhang Zetan Jiang Wenhao Ma Yuchen Sun Yiyang Chu Zilong Zhou Rui Liu Jian Li Shi-ting Li Ping Gao Huafeng Zhang |
| author_sort | Ling Ye |
| collection | DOAJ |
| description | Summary: Metabolic enzymes play significant roles in the pathogenesis of various cancers through both canonical and noncanonical functions. Hexokinase domain-containing protein 1 (HKDC1) functions beyond glucose metabolism, but its underlying mechanisms in tumorigenesis are not fully understood. Here, we demonstrate that nuclear-localized HKDC1 acts as a protein kinase to promote hepatocellular carcinoma (HCC) cell proliferation. Mechanistically, HKDC1 phosphorylates RB binding protein 5 (RBBP5) at Ser497, which is crucial for MLL1 complex assembly and subsequent histone H3 lysine 4 trimethylation (H3K4me3) modification. This leads to the transcriptional activation of mitosis-related genes, thereby driving cell cycle progression and proliferation. Notably, targeting HKDC1’s protein kinase activity, but not its HK activity, blocks RBBP5 phosphorylation and suppresses tumor growth. Clinical analysis further reveals that RBBP5 phosphorylation positively correlates with HKDC1 levels and poor HCC prognosis. These findings highlight the protein kinase function of HKDC1 in the activation of H3K4me3, gene expression, and HCC progression. |
| format | Article |
| id | doaj-art-753fcbb14b344cc6b1f34bb3ba488554 |
| institution | Kabale University |
| issn | 2211-1247 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj-art-753fcbb14b344cc6b1f34bb3ba4885542025-02-02T05:27:05ZengElsevierCell Reports2211-12472025-02-01442115250Nuclear-localized HKDC1 promotes hepatocellular carcinoma through phosphorylating RBBP5 to upregulate H3K4me3Ling Ye0Shengqi Shen1Qiankun Mao2Hui Lu3Haiying Liu4Pinggen Zhang5Zetan Jiang6Wenhao Ma7Yuchen Sun8Yiyang Chu9Zilong Zhou10Rui Liu11Jian Li12Shi-ting Li13Ping Gao14Huafeng Zhang15Department of General Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, ChinaMedical Research Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou 510080, ChinaDepartment of General Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, ChinaDepartment of General Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, ChinaDepartment of General Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, ChinaDepartment of General Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, ChinaDepartment of General Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China; Key Laboratory of Immune Response and Immunotherapy, School of Basic Medical Sciences, Division of Life Science and Medicine, University of Science and Technology of China, Hefei 230027, ChinaDepartment of General Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, ChinaDepartment of General Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, ChinaDepartment of General Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, ChinaDepartment of General Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, ChinaDepartment of General Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, ChinaDepartment of General Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, ChinaMedical Research Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou 510080, ChinaMedical Research Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou 510080, China; Corresponding authorDepartment of General Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China; Key Laboratory of Immune Response and Immunotherapy, School of Basic Medical Sciences, Division of Life Science and Medicine, University of Science and Technology of China, Hefei 230027, China; Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei 230601, China; Anhui Key Laboratory of Molecular Oncology, Hefei 230026, China; Corresponding authorSummary: Metabolic enzymes play significant roles in the pathogenesis of various cancers through both canonical and noncanonical functions. Hexokinase domain-containing protein 1 (HKDC1) functions beyond glucose metabolism, but its underlying mechanisms in tumorigenesis are not fully understood. Here, we demonstrate that nuclear-localized HKDC1 acts as a protein kinase to promote hepatocellular carcinoma (HCC) cell proliferation. Mechanistically, HKDC1 phosphorylates RB binding protein 5 (RBBP5) at Ser497, which is crucial for MLL1 complex assembly and subsequent histone H3 lysine 4 trimethylation (H3K4me3) modification. This leads to the transcriptional activation of mitosis-related genes, thereby driving cell cycle progression and proliferation. Notably, targeting HKDC1’s protein kinase activity, but not its HK activity, blocks RBBP5 phosphorylation and suppresses tumor growth. Clinical analysis further reveals that RBBP5 phosphorylation positively correlates with HKDC1 levels and poor HCC prognosis. These findings highlight the protein kinase function of HKDC1 in the activation of H3K4me3, gene expression, and HCC progression.http://www.sciencedirect.com/science/article/pii/S221112472500021XCP: Cancer |
| spellingShingle | Ling Ye Shengqi Shen Qiankun Mao Hui Lu Haiying Liu Pinggen Zhang Zetan Jiang Wenhao Ma Yuchen Sun Yiyang Chu Zilong Zhou Rui Liu Jian Li Shi-ting Li Ping Gao Huafeng Zhang Nuclear-localized HKDC1 promotes hepatocellular carcinoma through phosphorylating RBBP5 to upregulate H3K4me3 Cell Reports CP: Cancer |
| title | Nuclear-localized HKDC1 promotes hepatocellular carcinoma through phosphorylating RBBP5 to upregulate H3K4me3 |
| title_full | Nuclear-localized HKDC1 promotes hepatocellular carcinoma through phosphorylating RBBP5 to upregulate H3K4me3 |
| title_fullStr | Nuclear-localized HKDC1 promotes hepatocellular carcinoma through phosphorylating RBBP5 to upregulate H3K4me3 |
| title_full_unstemmed | Nuclear-localized HKDC1 promotes hepatocellular carcinoma through phosphorylating RBBP5 to upregulate H3K4me3 |
| title_short | Nuclear-localized HKDC1 promotes hepatocellular carcinoma through phosphorylating RBBP5 to upregulate H3K4me3 |
| title_sort | nuclear localized hkdc1 promotes hepatocellular carcinoma through phosphorylating rbbp5 to upregulate h3k4me3 |
| topic | CP: Cancer |
| url | http://www.sciencedirect.com/science/article/pii/S221112472500021X |
| work_keys_str_mv | AT lingye nuclearlocalizedhkdc1promoteshepatocellularcarcinomathroughphosphorylatingrbbp5toupregulateh3k4me3 AT shengqishen nuclearlocalizedhkdc1promoteshepatocellularcarcinomathroughphosphorylatingrbbp5toupregulateh3k4me3 AT qiankunmao nuclearlocalizedhkdc1promoteshepatocellularcarcinomathroughphosphorylatingrbbp5toupregulateh3k4me3 AT huilu nuclearlocalizedhkdc1promoteshepatocellularcarcinomathroughphosphorylatingrbbp5toupregulateh3k4me3 AT haiyingliu nuclearlocalizedhkdc1promoteshepatocellularcarcinomathroughphosphorylatingrbbp5toupregulateh3k4me3 AT pinggenzhang nuclearlocalizedhkdc1promoteshepatocellularcarcinomathroughphosphorylatingrbbp5toupregulateh3k4me3 AT zetanjiang nuclearlocalizedhkdc1promoteshepatocellularcarcinomathroughphosphorylatingrbbp5toupregulateh3k4me3 AT wenhaoma nuclearlocalizedhkdc1promoteshepatocellularcarcinomathroughphosphorylatingrbbp5toupregulateh3k4me3 AT yuchensun nuclearlocalizedhkdc1promoteshepatocellularcarcinomathroughphosphorylatingrbbp5toupregulateh3k4me3 AT yiyangchu nuclearlocalizedhkdc1promoteshepatocellularcarcinomathroughphosphorylatingrbbp5toupregulateh3k4me3 AT zilongzhou nuclearlocalizedhkdc1promoteshepatocellularcarcinomathroughphosphorylatingrbbp5toupregulateh3k4me3 AT ruiliu nuclearlocalizedhkdc1promoteshepatocellularcarcinomathroughphosphorylatingrbbp5toupregulateh3k4me3 AT jianli nuclearlocalizedhkdc1promoteshepatocellularcarcinomathroughphosphorylatingrbbp5toupregulateh3k4me3 AT shitingli nuclearlocalizedhkdc1promoteshepatocellularcarcinomathroughphosphorylatingrbbp5toupregulateh3k4me3 AT pinggao nuclearlocalizedhkdc1promoteshepatocellularcarcinomathroughphosphorylatingrbbp5toupregulateh3k4me3 AT huafengzhang nuclearlocalizedhkdc1promoteshepatocellularcarcinomathroughphosphorylatingrbbp5toupregulateh3k4me3 |