Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
Technion Integrated Cancer Center, Faculty of Medicine, Technion Institute of Technology, Haifa, Israel.
Mol Cancer Res. 2020 Oct;18(10):1560-1573. doi: 10.1158/1541-7786.MCR-20-0291. Epub 2020 Jun 22.
Mechanisms regulating nuclear organization control fundamental cellular processes, including the cell and chromatin organization. Their disorganization, including aberrant nuclear architecture, has been often implicated in cellular transformation. Here, we identify Lamin A, among proteins essential for nuclear architecture, as SPANX (sperm protein associated with the nucleus on the X chromosome), a cancer testis antigen previously linked to invasive tumor phenotypes, interacting protein in melanoma. SPANX interaction with Lamin A was mapped to the immunoglobulin fold-like domain, a region critical for Lamin A function, which is often mutated in laminopathies. SPANX downregulation in melanoma cell lines perturbed nuclear organization, decreased cell viability, and promoted senescence-associated phenotypes. Moreover, SPANX knockdown (KD) in melanoma cells promoted proliferation arrest, a phenotype mediated in part by IRF3/IL1A signaling. SPANX KD in melanoma cells also prompted the secretion of IL1A, which attenuated the proliferation of naïve melanoma cells. Identification of SPANX as a nuclear architecture complex component provides an unexpected insight into the regulation of Lamin A and its importance in melanoma. IMPLICATIONS: SPANX, a testis protein, interacts with LMNA and controls nuclear architecture and melanoma growth.
调节核组织的机制控制着基本的细胞过程，包括细胞和染色质组织。它们的紊乱，包括异常的核结构，常常与细胞转化有关。在这里，我们确定核结构所必需的蛋白质之一 lamin A 是 SPANX（与 X 染色体上的核相关的精子蛋白），这是一种先前与侵袭性肿瘤表型相关的癌症睾丸抗原，也是黑色素瘤中的相互作用蛋白。SPANX 与 lamin A 的相互作用被映射到免疫球蛋白折叠样结构域，这是 lamin A 功能的关键区域，在 laminopathies 中经常发生突变。在黑色素瘤细胞系中下调 SPANX 扰乱了核组织，降低了细胞活力，并促进了衰老相关表型。此外，在黑色素瘤细胞中敲低 SPANX（KD）促进了增殖停滞，这一表型部分是由 IRF3/IL1A 信号介导的。黑色素瘤细胞中 SPANX 的 KD 还促使 IL1A 的分泌，从而减弱了幼稚黑色素瘤细胞的增殖。将 SPANX 鉴定为核架构复合物的组成部分，为调节 lamin A 及其在黑色素瘤中的重要性提供了一个意想不到的见解。意义：SPANX，一种睾丸蛋白，与 LMNA 相互作用，控制核架构和黑色素瘤的生长。
