Biomedical Science Research Laboratory, Department of Basic Sciences, Faculty of Medicine, Universidad Católica de la Santísima Concepción, Concepción 4090541, Chile.
Biochemistry, Faculty of Pharmacy, Universidad de Concepción, Concepción 4070383, Chile.
Int J Mol Sci. 2024 Jan 12;25(2):944. doi: 10.3390/ijms25020944.
NSD3 (nuclear receptor-binding SET domain protein 3) is a member of the NSD histone methyltransferase family of proteins. In recent years, it has been identified as a potential oncogene in certain types of cancer. The NSD3 gene encodes three isoforms, the long version (NSD3L), a short version (NSD3S) and the WHISTLE isoforms. Importantly, the NSD3S isoform corresponds to the N-terminal region of the full-length protein, lacking the methyltransferase domain. The chromosomal location of NSD3 is frequently amplified across cancer types, such as breast, lung, and colon, among others. Recently, this amplification has been correlated to a chromothripsis event, that could explain the different NSD3 alterations found in cancer. The fusion proteins containing NSD3 have also been reported in leukemia (NSD3-NUP98), and in NUT (nuclear protein of the testis) midline carcinoma (NSD3-NUT). Its role as an oncogene has been described by modulating different cancer pathways through its methyltransferase activity, or the short isoform of the protein, through protein interactions. Specifically, in this review we will focus on the functions that have been characterized as methyltransferase dependent, and those that have been correlated with the expression of the NSD3S isoform. There is evidence that both the NSD3L and NSD3S isoforms are relevant for cancer progression, establishing NSD3 as a therapeutic target. However, further functional studies are needed to differentiate NSD3 oncogenic activity as dependent or independent of the catalytic domain of the protein, as well as the contribution of each isoform and its clinical significance in cancer progression.
NSD3（核受体结合 SET 域蛋白 3）是 NSD 组蛋白甲基转移酶家族蛋白的成员。近年来，它已被确定为某些类型癌症的潜在癌基因。NSD3 基因编码三个异构体，长型（NSD3L）、短型（NSD3S）和 WHISTLE 异构体。重要的是，NSD3S 异构体对应全长蛋白的 N 端区域，缺乏甲基转移酶结构域。NSD3 的染色体位置在多种癌症类型中经常扩增，如乳腺癌、肺癌和结肠癌等。最近，这种扩增与染色体重排事件相关，这可以解释在癌症中发现的不同 NSD3 改变。含有 NSD3 的融合蛋白也在白血病（NSD3-NUP98）和 NUT（睾丸核蛋白）中线癌（NSD3-NUT）中被报道。其作为癌基因的作用已通过其甲基转移酶活性或通过蛋白相互作用的短型蛋白来描述，通过调节不同的癌症途径。具体而言，在本综述中，我们将重点关注已被描述为依赖于甲基转移酶的功能，以及与 NSD3S 异构体表达相关的功能。有证据表明，NSD3L 和 NSD3S 异构体都与癌症进展有关，这确立了 NSD3 作为治疗靶点的地位。然而，需要进一步的功能研究来区分 NSD3 的致癌活性是否依赖于或独立于蛋白的催化结构域，以及每个异构体的贡献及其在癌症进展中的临床意义。
