UBE4B modulates BET inhibitor sensitivity via KLHL22-JAK2-PIM1 axis in hepatocellular carcinoma
文献类型：期刊论文
| 作者 | Wang, Li1,2; Huan, Xia-Juan1; Song, Shan-Shan1; Bao, Xu-Bin1; Tian, Chang-Qing1; Miao, Ze-Hong1,2; Wang, Ying-Qing1,2
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| 刊名 | BIOCHEMICAL PHARMACOLOGY
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| 出版日期 | 2025-07-01 |
| 卷号 | 237页码:19 |
| 关键词 | UBE4B BET inhibitors Resistance KLHL22 JAK2 |
| ISSN号 | 0006-2952 |
| DOI | 10.1016/j.bcp.2025.116943 |
| 英文摘要 | Ubiquitination factor E4B (UBE4B) is crucial to the high mortality rate and poor prognosis associated with hepatocellular carcinoma (HCC). Evidence suggests that aberrant epigenetic modifications significantly contribute to HCC carcinogenesis, making epigenetic mechanisms a promising area for therapeutic intervention. However, the precise role of UBE4B in the epigenetic dysregulation observed in HCC remains elusive. In this study, we silenced UBE4B in HCC cells and exposed them to a panel of epigenetic compounds. Notably, only bromodomain and extraterminal inhibitors (BETis) exhibited resistance to UBE4B silencing, while restoring UBE4B expression partially reversed this resistance. Furthermore, UBE4B deletion led to decreased growth rates and impaired proliferation, resulting in cell cycle arrest and diminished tumorigenicity. However, this deletion did not affect the cell cycle arrest induced by BETi. Interestingly, KLHL22, a ubiquitin substrate of UBE4B, accumulated in UBE4B-deleted cells. Knockdown of KLHL22 restored sensitivity to BETi, accompanied by downregulation of JAK2 and upregulation of its negative regulator, LNK. Additionally, UBE4B deletion resulted in decreased LNK expression, and LNK knockdown increased JAK2 expression and mediated resistance to BETi. Increased JAK2 subsequently targeted PIM1, further reducing the inhibitory effect of BETi. Directly silencing PIM1 in UBE4Bdeleted cells restored BETi sensitivity. Overall, our findings provide novel insights into the relationship between UBE4B expression and BETi sensitivity, which is mediated through the KLHL22-JAK2-PIM1 regulatory axis. These findings not only deepen our understanding of the mechanisms underlying HCC progression but also suggest that targeting this axis may present a promising therapeutic strategy for enhancing the treatment outcomes of HCC. |
| WOS关键词 | UBIQUITINATION FACTOR E4B ; TUMOR-CELLS ; EXPRESSION ; GROWTH ; MYC ; DEGRADATION ; CONTRIBUTES ; SUPPRESSION ; PROGNOSIS ; KINASES |
| 资助项目 | National Natural Science Foundation of China[82073865] ; National Natural Science Foundation of China[81773764] ; Science and Technology Commission of Shanghai Municipality[20ZR1468100] ; Shanghai Institute of Materia Medica, Chinese Academy of Sciences[SIMM0320231010] ; State Key Laboratory of Drug Research |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:001476319600001 |
| 出版者 | PERGAMON-ELSEVIER SCIENCE LTD |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/317521]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Wang, Ying-Qing |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, Canc Res Ctr, State Key Lab Drug Res, 501 Haike Rd, Shanghai 201203, Peoples R China 2.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China |
| 推荐引用方式 GB/T 7714 | Wang, Li,Huan, Xia-Juan,Song, Shan-Shan,et al. UBE4B modulates BET inhibitor sensitivity via KLHL22-JAK2-PIM1 axis in hepatocellular carcinoma[J]. BIOCHEMICAL PHARMACOLOGY,2025,237:19. |
| APA | Wang, Li.,Huan, Xia-Juan.,Song, Shan-Shan.,Bao, Xu-Bin.,Tian, Chang-Qing.,...&Wang, Ying-Qing.(2025).UBE4B modulates BET inhibitor sensitivity via KLHL22-JAK2-PIM1 axis in hepatocellular carcinoma.BIOCHEMICAL PHARMACOLOGY,237,19. |
| MLA | Wang, Li,et al."UBE4B modulates BET inhibitor sensitivity via KLHL22-JAK2-PIM1 axis in hepatocellular carcinoma".BIOCHEMICAL PHARMACOLOGY 237(2025):19. |
入库方式： OAI收割
来源：上海药物研究所
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