Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang, 222005, China.
Cell Death Dis. 2021 Jul 31;12(8):758. doi: 10.1038/s41419-021-04040-9.
Heterogeneous nuclear ribonucleoprotein L (hnRNPL) is a type of RNA binding protein that highly expressed in a variety of tumors and plays a vital role in tumor progression. However, its post-translational regulation through ubiquitin-mediated proteolysis and the cellular mechanism responsible for its proteasomal degradation remains unclear. F-box proteins (FBPs) function as the substrate recognition subunits of SCF ubiquitin ligase complexes and directly bind to substrates. The aberrant expression or mutation of FBPs will lead to the accumulation of its substrate proteins that often involved in tumorigenesis. Here we discover FBXO16, an E3 ubiquitin ligase, to be a tumor suppressor in ovarian cancer, and patients with the relatively high expression level of FBXO16 have a better prognosis. Silencing or depleting FBXO16 significantly enhanced ovarian cancer cell proliferation, clonogenic survival, and cell invasion by activating multiple oncogenic pathways. This function requires the F-box domain of FBXO16, through which FBXO16 assembles a canonical SCF ubiquitin ligase complex that constitutively targets hnRNPL for degradation. Depletion of hnRNPL is sufficient to inactive multiple oncogenic signaling regulated by FBXO16 and prevent the malignant behavior of ovarian cancer cells caused by FBXO16 deficiency. FBXO16 interacted with the RRM3 domain of hnRNPL via its C-terminal region to trigger the proteasomal degradation of hnRNPL. Failure to degrade hnRNPL promoted ovarian cancer cell proliferation in vitro and tumor growth vivo, phenocopying the deficiency of FBXO16 in ovarian cancer.
异质核核糖核蛋白 L（hnRNPL）是一种 RNA 结合蛋白，在多种肿瘤中高度表达，在肿瘤进展中发挥重要作用。然而，其通过泛素介导的蛋白水解的翻译后调节以及负责其蛋白酶体降解的细胞机制尚不清楚。F -box 蛋白（FBPs）作为 SCF 泛素连接酶复合物的底物识别亚基起作用，并直接与底物结合。FBPs 的异常表达或突变会导致其底物蛋白的积累，这些蛋白通常涉及肿瘤发生。在这里，我们发现 FBXO16，一种 E3 泛素连接酶，是卵巢癌的肿瘤抑制因子，并且具有相对高表达水平 FBXO16 的患者具有更好的预后。沉默或耗尽 FBXO16 通过激活多种致癌途径，显著增强卵巢癌细胞的增殖、集落形成存活和细胞侵袭。该功能需要 FBXO16 的 F-box 结构域，通过该结构域，FBXO16 组装了一个规范的 SCF 泛素连接酶复合物，该复合物持续靶向 hnRNPL 进行降解。hnRNPL 的耗尽足以使 FBXO16 调节的多种致癌信号失活，并防止由 FBXO16 缺乏引起的卵巢癌细胞的恶性行为。FBXO16 通过其 C 末端区域与 hnRNPL 的 RRM3 结构域相互作用，触发 hnRNPL 的蛋白酶体降解。未能降解 hnRNPL 促进了卵巢癌细胞在体外的增殖和体内肿瘤的生长，模拟了 FBXO16 在卵巢癌中的缺失。
Zotero 插件
