Histone variant H3 .3 promotes metastasis in alveolar rhabdomyosarcoma

Autor: Nandini Karthik, Jane Jia Hui Lee, Joshua Ling Jun Soon, Hsin Yao Chiu, Amos Hong Pheng Loh, Derrick Sek Tong Ong, Wai Leong Tam, Reshma Taneja
Rok vydání: 2023
Předmět:
Zdroj: The Journal of Pathology. 259:342-356
ISSN: 1096-9896
0022-3417
DOI: 10.1002/path.6048
Popis: The relatively quiet mutational landscape of rhabdomyosarcoma (RMS) suggests that epigenetic deregulation could be central to oncogenesis and tumour aggressiveness. Histone variants have long been recognised as important epigenetic regulators of gene expression. However, the role of histone variants in RMS has not been studied hitherto. In this study, we show that histone variant H3.3 is overexpressed in alveolar rhabdomyosarcoma (ARMS), an aggressive subtype of RMS. Functionally, knockdown of H3F3A, which encodes for H3.3, significantly impairs the ability of ARMS cells to undertake migration and invasion and reduces Rho activation. In addition, a striking reduction in metastatic tumour burden and improved survival is apparent in vivo. Using RNA-sequencing and ChIP-sequencing analyses, we identified Melanoma Cell Adhesion Molecule (MCAM/CD146) as a direct downstream target of H3.3. Loss of H3.3 resulted in a reduction in the presence of active marks, and an increase in the occupancy of H1 at the MCAM promoter. Cell migration and invasion were rescued in H3F3A-depleted cells through MCAM overexpression. Moreover, we identified G9a, a lysine methyltransferase encoded by EHMT2, as an upstream regulator of H3F3A. Therefore, this study identifies a novel H3.3 dependent axis involved in ARMS metastasis. These findings establish the potential of MCAM as a therapeutic target for high-risk ARMS patients. This article is protected by copyright. All rights reserved.
Databáze: OpenAIRE
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