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- Title
High G9a Expression in DLBCL and Its Inhibition by Niclosamide to Induce Autophagy as a Therapeutic Approach.
- Authors
Hsu, Chin-Mu; Chang, Kung-Chao; Chuang, Tzer-Ming; Chu, Man-Ling; Lin, Pei-Wen; Liu, Hsiao-Sheng; Kao, Shih-Yu; Liu, Yi-Chang; Huang, Chien-Tzu; Wang, Min-Hong; Yeh, Tsung-Jang; Gau, Yuh-Ching; Du, Jeng-Shiun; Wang, Hui-Ching; Cho, Shih-Feng; Hsiao, Chi-En; Tsai, Yuhsin; Hsiao, Samuel Yien; Hung, Li-Chuan; Yen, Chia-Hung
- Abstract
Simple Summary: Diffuse large B-cell lymphoma (DLBCL) is a prevalent hematological malignancy which is characterized by rapid cancer cell growth and aggressive progression. The standard treatment is R-CHOP, which offers limited prognosis improvement for only 60% of patients. This study aimed to identify DLBCL tumor markers and to explore cytotoxic medicine. The results demonstrated significant upregulation of G9a/EHMT2 mRNA in DLBCL. Niclosamide effectively suppressed G9a expression, modulated autophagy-related gene expression (p62, BECN1, and LC3), and impeded DLBCL cell proliferation. Analysis of clinical specimens and patients' information revealed a positive correlation between G9a protein levels and DLBCL staging, indicating its potential as a prognostic biomarker. Our study provides valuable insight that highlights the potential of G9a as a therapeutic target and niclosamide as a potential treatment to combat DLBCL. Background: Diffuse large B-cell lymphoma (DLBCL) is a malignant lymphoid tumor disease that is characterized by heterogeneity, but current treatment does not benefit all patients, which highlights the need to identify oncogenic genes and appropriate drugs. G9a is a histone methyltransferase that catalyzes histone H3 lysine 9 (H3K9) methylation to regulate gene function and expression in various cancers. Methods: TCGA and GTEx data were analyzed using the GEPIA2 platform. Cell viability under drug treatment was assessed using Alamar Blue reagent; the interaction between G9a and niclosamide was assessed using molecular docking analysis; mRNA and protein expression were quantified in DLBCL cell lines. Finally, G9a expression was quantified in 39 DLBCL patient samples. Results: The TCGA database analysis revealed higher G9a mRNA expression in DLBCL compared to normal tissues. Niclosamide inhibited DLBCL cell line proliferation in a time- and dose-dependent manner, reducing G9a expression and increasing p62, BECN1, and LC3 gene expression by autophagy pathway regulation. There was a correlation between G9a expression in DLBCL samples and clinical data, showing that advanced cancer stages exhibited a higher proportion of G9a-expressing cells. Conclusion: G9a overexpression is associated with tumor progression in DLBCL. Niclosamide effectively inhibits DLBCL growth by reducing G9a expression via the cellular autophagy pathway; therefore, G9a is a potential molecular target for the development of therapeutic strategies for DLBCL.
- Subjects
METHYLTRANSFERASES; AUTOPHAGY; CARCINOGENESIS; B cell lymphoma; GENE expression; CANCER patients; CELL survival; COMPARATIVE studies; MESSENGER RNA; CELL proliferation; RESEARCH funding; CELL lines; COMPUTER-assisted molecular modeling; AMIDES
- Publication
Cancers, 2023, Vol 15, Issue 16, p4150
- ISSN
2072-6694
- Publication type
Article
- DOI
10.3390/cancers15164150