Cancer-associated SPOP mutations enlarge nuclear size and facilitate nuclear envelope rupture upon farnesyltransferase inhibitor treatment
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
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
View: Text | PDF
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

×

Figure 6

SPOP mutant cells are hypersensitive to farnesyltransferase inhibition.

Options: View larger image (or click on image) Download as PowerPoint
SPOP mutant cells are hypersensitive to farnesyltransferase inhibition. ...
(A–D) Dose-response survival curves of PC-3 (A and B) and HeLa (C and D) cell lines infected with lentivirus expressing HA-WT, F102C, or F133V SPOP exposed to increasing concentrations of tipifarnib (A and C) or lonafarnib (B and D). Data are reported as the mean ± SD of 3 independent experiments (n = 3). (E–H) Colony-formation assays in PC-3 (E and F) and HeLa (G and H) cell lines infected with lentivirus expressing HA-WT, F102C, or F133V SPOP. The number of colonies was counted. Representative colonies are shown in (E and G); quantification data are shown in (F and H). Data are presented as the mean ± SD of 3 independent experiments (n = 3). (I and J) SPOP WT or SPOP F133L PDX tumors were transplanted subcutaneously into SCID mice and treated with lonafarnib (20 mg/kg, twice daily by oral gavage) or vehicle. Mice were treated for 18 days and then sacrificed. Tumors were isolated and are shown in (I) and their volumes (n = 5) are shown in (J). All data are reported as mean ± SD. (K) Schematic illustrating the mechanism of FTIs effectively killing SPOP-mutant cells. *P < 0.05, **P < 0.01, and ***P < 0.001 by 2-way ANOVA (A–D) or 1-way ANOVA followed by Dunnett’s multiple comparisons test (F and H) or 2-way ANOVA followed by Tukey’s multiple comparisons test (J).