Bajaj Upasana, Das Dipanwita, Leung Jia Yu, Binti Abdul Rashi Nurul Fateha, Taneja Reshma
Department of Physiology, Healthy Longevity and NUS Centre for Cancer Research Translation Research Program, Yong Loo Lin School of Medicine, National University of Singapore (NUS), 2 Medical Drive, MD9, Singapore, 117593, Republic of Singapore.
Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore (NUS), National University Hospital (NUH), 5 Lower Kent Ridge Road, Singapore, 119074, Republic of Singapore.
Br J Cancer. 2025 Jun 4. doi: 10.1038/s41416-025-03066-6.
Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma. When metastatic, survival of children with RMS is less than 20% and has remained unchanged over two decades. No targeted drug therapy is available for these cancers. Genomic analysis has revealed a low incidence of somatic mutations in RMS. Epigenetic modifiers thus play important roles in driving oncogenesis. In this study, we examined the role of EHMT1 in fusion- negative embryonal rhabdomyosarcoma (ERMS), the most frequent subtype of RMS.
We performed transcriptomic and phenotypic analysis in vitro and in vivo using EHMT1 depleted cells as well as that of its target gene SOX8.
EHMT1 was found to enhance migration and invasion of ERMS cells in vitro and metastasis in vivo. SOX8, a transcription factor that has key roles in cellular motility was significantly decreased upon EHMT1 loss. Consistently, SOX8 depletion phenotypically mimicked EHMT1 loss. Moreover, RNA Sequencing of SOX8 depleted cells showed down regulation of several integrin genes. Mechanistically, EHMT1 was found to upregulate SOX8 via regulation of BRD4 expression, and consequently increased BRD4 occupancy at the SOX8 promoter.
Our study reveals a novel EHMT1-SOX8 axis that mediates metastasis in ERMS.
横纹肌肉瘤（RMS）是最常见的儿童软组织肉瘤。发生转移时，RMS患儿的生存率低于20%，且二十多年来一直没有变化。这些癌症尚无靶向药物治疗。基因组分析显示RMS中体细胞突变的发生率较低。因此，表观遗传修饰因子在驱动肿瘤发生中起重要作用。在本研究中，我们研究了EHMT1在融合阴性胚胎性横纹肌肉瘤（ERMS）中的作用，ERMS是RMS最常见的亚型。
我们使用EHMT1缺失的细胞及其靶基因SOX8进行了体外和体内的转录组学和表型分析。
发现EHMT1在体外增强ERMS细胞的迁移和侵袭能力，在体内促进转移。SOX8是一种在细胞运动中起关键作用的转录因子，在EHMT1缺失时显著降低。一致地，SOX8缺失在表型上模拟了EHMT1缺失。此外，对SOX8缺失细胞的RNA测序显示几种整合素基因下调。从机制上讲，发现EHMT1通过调节BRD4表达上调SOX8，并因此增加BRD4在SOX8启动子上的占位。
我们的研究揭示了一种新的EHMT1-SOX8轴，该轴介导ERMS的转移。
