BCLAF1 binds SPOP to stabilize PD-L1 and promotes the development and immune escape of hepatocellular carcinoma
© 2024. The Author(s)..
Interaction between programmed death-1 (PD-1) ligand 1 (PD-L1) on tumor cells and PD-1 on T cells allows tumor cells to evade T cell-mediated immune surveillance. Strategies targeting PD-1/PD-L1 have shown clinical benefits in a variety of cancers. However, limited response rates in hepatocellular carcinoma (HCC) have prompted us to investigate the molecular regulation of PD-L1. Here, we identify B cell lymphoma-2-associated transcription factor 1 (BCLAF1) as a key PD-L1 regulator in HCC. Specifically, BCLAF1 interacts with SPOP, an E3 ligase that mediates the ubiquitination and degradation of PD-L1, thereby competitively inhibiting SPOP-PD-L1 interaction and subsequent ubiquitination and degradation of PD-L1. Furthermore, we determined an SPOP-binding consensus (SBC) motif mediating the BCLAF1-SPOP interaction on BCLAF1 protein and mutation of BCLAF1-SBC motif disrupts the regulation of the SPOP-PD-L1 axis. In addition, BCLAF1 expression was positively correlated with PD-L1 expression and negatively correlated with biomarkers of T cell activation, including CD3 and CD8, as well as with the level of immune cell infiltration in HCC tissues. Besides, BCLAF1 depletion leads to a significant reduction of PD-L1 expression in vitro, and this reduction of PD-L1 promoted T cell-mediated cytotoxicity. Notably, overexpression of BCLAF1 sensitized tumor cells to checkpoint therapy in an in vitro HCC cells-Jurkat cells co-culture model, whereas BCLAF1-SBC mutant decreased tumor cell sensitivity to checkpoint therapy, suggesting that BCLAF1 and its SBC motif serve as a novel therapeutic target for enhancing anti-tumor immunity in HCC.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:81 |
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| Enthalten in: |
Cellular and molecular life sciences : CMLS - 81(2024), 1 vom: 10. Feb., Seite 82 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Yu, Zongdong [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 14.02.2024 Date Revised 28.02.2024 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1007/s00018-024-05144-z |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM368296954 |
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| 245 | 1 | 0 | |a BCLAF1 binds SPOP to stabilize PD-L1 and promotes the development and immune escape of hepatocellular carcinoma |
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| 500 | |a Date Revised 28.02.2024 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2024. The Author(s). | ||
| 520 | |a Interaction between programmed death-1 (PD-1) ligand 1 (PD-L1) on tumor cells and PD-1 on T cells allows tumor cells to evade T cell-mediated immune surveillance. Strategies targeting PD-1/PD-L1 have shown clinical benefits in a variety of cancers. However, limited response rates in hepatocellular carcinoma (HCC) have prompted us to investigate the molecular regulation of PD-L1. Here, we identify B cell lymphoma-2-associated transcription factor 1 (BCLAF1) as a key PD-L1 regulator in HCC. Specifically, BCLAF1 interacts with SPOP, an E3 ligase that mediates the ubiquitination and degradation of PD-L1, thereby competitively inhibiting SPOP-PD-L1 interaction and subsequent ubiquitination and degradation of PD-L1. Furthermore, we determined an SPOP-binding consensus (SBC) motif mediating the BCLAF1-SPOP interaction on BCLAF1 protein and mutation of BCLAF1-SBC motif disrupts the regulation of the SPOP-PD-L1 axis. In addition, BCLAF1 expression was positively correlated with PD-L1 expression and negatively correlated with biomarkers of T cell activation, including CD3 and CD8, as well as with the level of immune cell infiltration in HCC tissues. Besides, BCLAF1 depletion leads to a significant reduction of PD-L1 expression in vitro, and this reduction of PD-L1 promoted T cell-mediated cytotoxicity. Notably, overexpression of BCLAF1 sensitized tumor cells to checkpoint therapy in an in vitro HCC cells-Jurkat cells co-culture model, whereas BCLAF1-SBC mutant decreased tumor cell sensitivity to checkpoint therapy, suggesting that BCLAF1 and its SBC motif serve as a novel therapeutic target for enhancing anti-tumor immunity in HCC | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a BCLAF1 | |
| 650 | 4 | |a Hepatocellular carcinoma | |
| 650 | 4 | |a Immunotherapy | |
| 650 | 4 | |a PD-L1 | |
| 650 | 4 | |a SPOP | |
| 650 | 7 | |a B7-H1 Antigen |2 NLM | |
| 650 | 7 | |a BCLAF1 protein, human |2 NLM | |
| 650 | 7 | |a Nuclear Proteins |2 NLM | |
| 650 | 7 | |a Programmed Cell Death 1 Receptor |2 NLM | |
| 650 | 7 | |a Repressor Proteins |2 NLM | |
| 650 | 7 | |a SPOP protein, human |2 NLM | |
| 650 | 7 | |a Tumor Suppressor Proteins |2 NLM | |
| 700 | 1 | |a Wu, Xiang |e verfasserin |4 aut | |
| 700 | 1 | |a Zhu, Jie |e verfasserin |4 aut | |
| 700 | 1 | |a Yan, Huan |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Yuxuan |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Hui |e verfasserin |4 aut | |
| 700 | 1 | |a Zhong, Yeling |e verfasserin |4 aut | |
| 700 | 1 | |a Lin, Man |e verfasserin |4 aut | |
| 700 | 1 | |a Ye, Ganghui |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Xinming |e verfasserin |4 aut | |
| 700 | 1 | |a Jin, Jiabei |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Kailang |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Jie |e verfasserin |4 aut | |
| 700 | 1 | |a Zhuang, Hui |e verfasserin |4 aut | |
| 700 | 1 | |a Lin, Ting |e verfasserin |4 aut | |
| 700 | 1 | |a He, Jian |e verfasserin |4 aut | |
| 700 | 1 | |a Lu, Changjiang |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Zeping |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Xie |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Hong |e verfasserin |4 aut | |
| 700 | 1 | |a Jin, Xiaofeng |e verfasserin |4 aut | |
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