Dreher Rachel D, Theisen Emily R
Abigail Wexner Research Institute, Center for Childhood Cancer and Blood Diseases, Nationwide Children's Hospital, Columbus, OH, United States.
Biomedical Sciences Graduate Program, College of Medicine, the Ohio State University, Columbus, OH, United States.
Front Oncol. 2023 Jan 4;12:1076581. doi: 10.3389/fonc.2022.1076581. eCollection 2022.
Sarcomas are a diverse group of tumors with numerous oncogenic drivers, and display varied clinical behaviors and prognoses. This complexity makes diagnosis and the development of new and effective treatments challenging. An incomplete understanding of both cell of origin and the biological drivers of sarcomas complicates efforts to develop clinically relevant model systems and find new molecular targets. Notably, the histone lysine specific demethylase 1 (LSD1) is overexpressed in a number of different sarcomas and is a potential therapeutic target in these malignancies. With the ability to modify histone marks, LSD1 is a key player in many protein complexes that epigenetically regulate gene expression. It is a largely context dependent enzyme, having vastly different and often opposing roles depending on the cellular environment and which interaction partners are involved. LSD1 has been implicated in the development of many different types of cancer, but its role in bone and soft tissue sarcomas remains poorly understood. In this review, we compiled what is known about the LSD1 function in various sarcomas, to determine where knowledge is lacking and to find what theme emerge to characterize how LSD1 is a key molecular driver in bone and soft tissue sarcoma. We further discuss the current clinical landscape for the development of LSD1 inhibitors and where sarcomas have been included in early clinical trials.
肉瘤是一组具有多种致癌驱动因素的肿瘤，表现出不同的临床行为和预后。这种复杂性使得诊断以及开发新的有效治疗方法具有挑战性。对肉瘤的起源细胞和生物学驱动因素的不完全理解，使得开发临床相关模型系统和寻找新的分子靶点变得复杂。值得注意的是，组蛋白赖氨酸特异性去甲基化酶1（LSD1）在多种不同的肉瘤中过表达，是这些恶性肿瘤中的一个潜在治疗靶点。LSD1具有修饰组蛋白标记的能力，是许多在表观遗传上调节基因表达的蛋白质复合物中的关键成员。它在很大程度上是一种依赖于环境的酶，根据细胞环境以及所涉及的相互作用伙伴的不同，具有截然不同且往往相反的作用。LSD1已被证明与许多不同类型癌症的发生发展有关，但其在骨肉瘤和软组织肉瘤中的作用仍知之甚少。在这篇综述中，我们汇总了关于LSD1在各种肉瘤中的功能的已知信息，以确定知识上的空白，并找出出现的主题，以描述LSD1如何成为骨肉瘤和软组织肉瘤的关键分子驱动因素。我们还进一步讨论了LSD1抑制剂开发的当前临床情况，以及肉瘤在早期临床试验中的纳入情况。
