Wang Zixi, Li Lei, Ye Qi, Lei Yuzeshi, Lu Mingming, Ye Leihong, Kang Jialu, Huang Wenyue, Xu Shan, Wang Ke, Liu Jing, Gao Yang, Wang Chenji, Ma Jian, Li Lei
Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
State Key Laboratory of Genetic Engineering, MOE Engineering Research Center of Gene Technology, Shanghai Engineering Research Center of Industrial Microorganisms, School of Life Sciences, Fudan University, Shanghai, China.
J Clin Invest. 2025 Jul 15;135(14). doi: 10.1172/JCI189048.
Nuclear size is crucial for cellular functions and often increases with malignancy. Irregular nuclei are linked to aggressive tumors, driven by genetic and epigenetic changes. However, the precise mechanisms controlling nuclear size are still not fully understood. In this study, we demonstrated that cancer-associated speckle-type POZ protein (SPOP) mutations enlarged nuclear size by reducing the protein level of lamin B2 (LMNB2), a key nuclear integrity protein. Mechanistically, SPOP bound to LMNB2 and promoted its mono-ubiquitination at lysine-484, which protected it from degradation by the E3 ubiquitin ligase WD repeat domain 26. SPOP mutations disrupted this process, leading to reduced LMNB2 levels and impaired nuclear envelope (NE) integrity. This compromised NE was more vulnerable to damage from farnesyltransferase inhibitors (FTIs), causing nuclear rupture in SPOP-mutant tumor cells. This study identified SPOP as a positive regulator of nuclear size; the findings suggest tumors with SPOP mutations may be vulnerable to FTI-based therapies.
细胞核大小对细胞功能至关重要，且通常会随着恶性肿瘤的发展而增大。不规则细胞核与侵袭性肿瘤相关，这是由基因和表观遗传变化驱动的。然而，控制细胞核大小的精确机制仍未完全了解。在本研究中，我们证明癌症相关的斑点型POZ蛋白（SPOP）突变通过降低关键的核完整性蛋白核纤层蛋白B2（LMNB2）的蛋白水平来扩大细胞核大小。从机制上来说，SPOP与LMNB2结合并促进其在赖氨酸484处的单泛素化，从而保护它不被E3泛素连接酶WD重复结构域26降解。SPOP突变破坏了这一过程，导致LMNB2水平降低和核膜（NE）完整性受损。这种受损的核膜更容易受到法尼基转移酶抑制剂（FTIs）的损伤，从而导致SPOP突变的肿瘤细胞发生核破裂。本研究确定SPOP是细胞核大小的正向调节因子；研究结果表明，具有SPOP突变的肿瘤可能对基于FTI的治疗敏感。
