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RBM30 recruits DOT1L to activate STAT1 transcription and drive immune evasion in hepatocellular carcinoma

Oncogene volume 44, pages 3955–3973 (2025)Cite this article

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Abstract

Programmed death ligand 1 (PD-L1) is a protein expressed in hepatocellular carcinoma (HCC) that drives immune evasion by binding to programmed death receptor 1 (PD-1) on activated T cells. Understanding PD-L1 regulation is essential to understand the immunosuppressive microenvironment for antitumor immunity. We screened ribonucleic acid (RNA)-binding motif proteins (RBMs). RBM30 can enhance PD-L1 expression in HCC cells. In this study, we found that high RBM30 expression in tumor tissues can drive HCC tumor immune evasion and accelerate disease progression via increased PD-L1 transcription. We conducted multiple molecular and high-throughput assays to elucidate the intrinsic molecular mechanisms by which RBM30 upregulates PD-L1 expression in HCC. RBM30 binds to DNA near the transcriptional start site of STAT1 and recruits DOT1L to promote H3K79me3 enrichment, enhancing its accessibility to upregulate STAT1 transcription, consequently activating the PD-L1 transcription. This enhances PD-L1 expression to facilitate immune evasion. These findings reveal the vital role of RBM30 in HCC immune evasion.

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Fig. 1: RBM30 upregulates programmed death ligand 1 (PD-L1) expression in hepatocellular carcinoma (HCC).
Fig. 2: High RBM30 expression in HCC is negatively associated with patient prognosis.
Fig. 3: RBM30 upregulates PD-L1 expression in HCC via the STAT1 signaling pathway.
Fig. 4: RBM30 upregulates PD-L1 expression in HCC via the STAT1 signaling pathway.
Fig. 5: RBM30 enhances the transcription of STAT1 by recruiting DOT1L to promote HCC immune evasion.
Fig. 6: RBM30 forms a heterodimer via its C-terminus interacting with the C-terminal domain of DOT1L.
Fig. 7: RBM30 and DOT1L enhances PD-L1 expression in HCC.
Fig. 8: RBM30 knockout enhances the efficacy of HCC immunotherapy.

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Data availability

Raw and processed sequencing data have been deposited at SRA database (PRJNA1089826) and are publicly available as of the date of publication. The rest of the data reported in this paper will be shared by the lead contact upon request. This paper does not report original code. Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request. All data generated or analyzed during this study are included in this published article and its supplementary information files, The high-throughput sequencing data generated in this study are publicly available at SRA datebase (PRJNA1089826).

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Acknowledgements

We sincerely thank the central Laboratory of Taizhou People’s Hospital Affiliated to Nanjing Medical University for the help of instruments and equipment. We thank Home for Researchers editorial team (www.home-for-researchers.com) for language editing service and drawing the pattern diagram.

Funding

This project was supported by National Natural Science Foundation of China (82303115), The Youth Fund of Taizhou People’s Hospital Affiliated to Nanjing Medical University (TZKY20240109), Scientific research start-up fund of Taizhou People’s Hospital (QDJJ202106), Taizhou Society Development Project, Jiangsu, China (TS202308), General Project of Jiangsu Provincial Health Commission (H2023030), China Postdoctoral Science Foundation (2024M751162), Top Talent Support Program for young and middle-aged people of Wuxi Health Committee (HB2023060).

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Author notes

  1. These authors contributed equally: Hexu Han, Chen Gong, Yue Zhang, Cuixia Liu.

Authors and Affiliations

  1. Department of Gastroenterology, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, Jiangsu, China

    Hexu Han, Cuixia Liu, Yifan Wang & Dakun Zhao

  2. Department of Gastroenterology, Taicang Affiliated Hospital of Soochow University, The First People’s Hospital of Taicang, Taicang, Jiangsu Province, China

    Chen Gong

  3. Clinical Medical Laboratory Center, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou, Jiangsu, China

    Yue Zhang

  4. Department of Oncology, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, Jiangsu, China

    Junxing Huang

  5. Wuxi Cancer Institute, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, China

    Zhicheng Gong

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Contributions

Zhicheng Gong and Hexu Han performed study concept and design; Hexu Han and Chen Gong completed the experimental part of the project; Yue Zhang and Cuixia Liu performed development of methodology and writing, review and revision of the paper; Junxing Huang provided acquisition, analysis and interpretation of data, and statistical analysis; Yifan Wang and Dakun Zhao provided technical and material support. All authors read and approved the final paper.

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Correspondence to Hexu Han, Junxing Huang or Zhicheng Gong.

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The experimental protocol was approved by the Institutional Ethics Review Board of The Affiliated Taizhou People’s Hospital of Nanjing Medical University (2022-008-01). Animal ethical certificates were approved by the Experimental Center of Jiangsu Hanjiang Biotechnology Co., Ltd (HJSW-23050302), and the animals were raised according to animal welfare laws.

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Han, H., Gong, C., Zhang, Y. et al. RBM30 recruits DOT1L to activate STAT1 transcription and drive immune evasion in hepatocellular carcinoma. Oncogene 44, 3955–3973 (2025). https://doi.org/10.1038/s41388-025-03550-6

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