Chromatin-binding protein HMGN1 promotes HCC tumorigenesis via histone methylation-induced <i>RALB</i> transcriptional suppression

Xiameng Su; Leirong Gu; Tingting Gao; Wanjin Chen; Ming Tan; Yuting Liu; Zhiling Wang; Xinyan Chen; Hui Zhang; Shengtao Cheng

doi:10.1016/j.jgg.2026.03.009

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Chromatin-binding protein HMGN1 promotes HCC tumorigenesis via histone methylation-induced RALB transcriptional suppression

doi: 10.1016/j.jgg.2026.03.009

a. Department of Clinical Laboratory, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China;
b. Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China

Funds:

This work was supported by National Natural Science Foundation of China (82473089 to STC)

Chongqing Natural Science Foundation (CSTB2024NSCQ-QCXMX0003 to STC)

and Scientific and Technological Research Program of Chongqing Municipal Education Commission (KJQN202300465 to STC). We thank American Journal Experts (AJE) for English language editing. The authors also thank the Laboratory Animal Center of Chongqing Medical University for mouse housing and care.

Received Date: 2025-07-24
Accepted Date: 2026-03-10
Rev Recd Date: 2026-03-08

Available Online: 2026-03-16

Abstract

Abstract

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide, with metastasis being the primary cause of its high mortality. The chromatin-binding protein, high mobility group nucleosome binding domain 1 (HMGN1), has been implicated in tumour progression, but its specific role and mechanism in HCC metastasis remain unclear. This study investigates the function of HMGN1 and its potential as a therapeutic target. Analysis of patient samples confirms an upregulation of HMGN1 in HCC tissues, correlating with advanced disease and poor prognosis. Functional assays demonstrate that HMGN1 promotes HCC metastasis in vitro and in vivo. Mechanistically, integrated RNA sequencing and chromatin immunoprecipitation sequencing analyses reveal that HMGN1 binds to the promoter of RAS-like proto-oncogene B (RALB) gene, recruiting the repressive histone mark H3K9me2 to epigenetically silence its transcription and drive metastasis. Therapeutically, a nanoparticle (NP) delivery system for siRNA against HMGN1 effectively silences its expression and inhibits metastasis in orthotopic liver xenograft tumour models. Our findings establish HMGN1 as a key epigenetic driver of HCC metastasis and highlight siRNA-nanoparticle targeting of HMGN1 as a promising precision therapeutic strategy.
- Hepatocellular carcinoma,
- metastasis,
- HMGN1,
- transcription,
- chromatin

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