Cancer-associated SPOP mutations enlarge nuclear size and facilitate nuclear envelope rupture upon farnesyltransferase inhibitor treatment
Zixi Wang, … , Jian Ma, Lei Li
Zixi Wang, … , Jian Ma, Lei Li
Published July 15, 2025
Citation Information: J Clin Invest. 2025;135(14):e189048. https://doi.org/10.1172/JCI189048.
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Research Article Cell biology

Cancer-associated SPOP mutations enlarge nuclear size and facilitate nuclear envelope rupture upon farnesyltransferase inhibitor treatment

Abstract

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.

Authors

Zixi Wang, Lei Li, Qi Ye, Yuzeshi Lei, Mingming Lu, Leihong Ye, Jialu Kang, Wenyue Huang, Shan Xu, Ke Wang, Jing Liu, Yang Gao, Chenji Wang, Jian Ma, Lei Li

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Figure 1

SPOP mutation increases cell nuclear volume.

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SPOP mutation increases cell nuclear volume. (A and B) Quantification of...
(A and B) Quantification of nuclear area from diagnostic slides from patients in the SPOP WT (n = 354) and SPOT mutant (MUT) (n = 40) groups from the TCGA prostate adenocarcinoma data set (37) (A) and patients in the SPOP WT (n = 404) and SPOP MUT (n = 51) groups from the TCGA uterine corpus endometrial carcinoma data set (50) (B). (C and D) Representative H&E staining (C) images of prostate cancer specimens from the SPOP WT (n = 80) and SPOP MUT (n = 20) groups and quantification data (D). Scale bars: 200 μm in ×10 fields; 40 μm in ×40 fields. (E and F) PC-3 cells infected with lentivirus expressing WT, F102C, or F133V SPOP were analyzed using 2D and 3D IF (E) and quantified (F). Scale bar: 50 μm. (G and H) Control or SPOP knockout PC-3 cells were analyzed using 2D and 3D IF (G) and quantification (H). Scale bar: 50 μm. Data are shown as the mean ± SD of 3 biological replicates (n > 200). (I) Co-IP analysis of indicated proteins in 293T cells transiently transfected with Flag-LMNA, LMNB1, or LMNB2. (J) Co-IP analysis of endogenous proteins in 293T cells using indicated antibodies. (K) A LMNB2 structure diagram showing 2 putative evolutionally conserved SBC motifs (SBC1 and SBC2) located at the C-terminal of LMNB2. (L) Co-IP analysis of indicated proteins in 293T cells transiently transfected with Flag-LMNB2 WT, ΔSBC1, or ΔSBC2. *P < 0.05, ***P < 0.001 by Mann-Whitney test (A, B, D, and H) or 1-way ANOVA followed by Dunnett’s multiple comparisons test (F).