Histone variant H3.3 promotes metastasis in alveolar rhabdomyosarcoma.
Nandini KarthikJane Jia Hui LeeJoshua Ling Jun SoonHsin Yao ChiuAmos Hong Pheng LohDerrick Sek Tong OngWai Leong TamReshma TanejaPublished in: The Journal of pathology (2022)
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.
Keyphrases
- dna methylation
- gene expression
- single cell
- genome wide
- induced apoptosis
- transcription factor
- copy number
- cell adhesion
- end stage renal disease
- newly diagnosed
- small cell lung cancer
- high throughput
- squamous cell carcinoma
- peritoneal dialysis
- cell proliferation
- oxidative stress
- endoplasmic reticulum stress
- magnetic resonance
- prognostic factors
- cell death
- free survival
- bone marrow
- magnetic resonance imaging
- smooth muscle
- diffusion weighted imaging