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Abstract
Next-generation sequencing of the exome and genome of prostate cancers has identified numerous genetic alternations. SPOP (Speckle-type POZ Protein) was one of the most frequently mutated genes in primary prostate cancer, suggesting SPOP is a potential driver of prostate cancer development and progression. However, how SPOP mutations contribute to prostate cancer pathogenesis remains poorly understood. SPOP acts as an adaptor protein of the CUL3-RBX1 E3 ubiquitin ligase complex that generally recruits substrates for ubiquitination and subsequent degradation. ER-localized isoform of the formin protein inverted formin 2 (INF2) mediates actin polymerization at ER-mitochondria intersections and facilitates DRP1 recruitment to mitochondria, which is a critical step in mitochondrial fission. Here, we revealed that SPOP recognizes a Ser/Thr (S/T)-rich motif in the C-terminal region of INF2 and triggers atypical polyubiquitination of INF2. These ubiquitination modifications do not lead to INF2 instability, but rather reduces INF2 localization in ER and mitochondrially associated DRP1 puncta formation, therefore abrogates its ability to facilitate mitochondrial fission. INF2 mutant escaping from SPOP-mediated ubiquitination is more potent in prompting mitochondrial fission. Moreover, prostate cancer-associated SPOP mutants increase INF2 localization in ER and promote mitochondrial fission, probably through a dominant-negative effect to inhibit endogenous SPOP. Moreover, INF2 is important for SPOP inactivation-induced prostate cancer cell migration and invasion. These findings reveal novel molecular events underlying the regulation of INF2 function and localization, and provided insights in understanding the relationship between SPOP mutations and dysregulation of mitochondrial dynamics in prostate cancer.
Highlights
Large-scale exome/genome sequencing studies have recently revealed that recurrent mutations in the SPOP gene occur in up to 15% of prostate cancers [1,2,3,4]
SPOP gene was frequently altered by somatic point mutations in a distinct molecular subclass of prostate cancer, the precise role that SPOP mutation plays in the development of prostate cancer is unclear
Unbalanced mitochondrial fission and fusion events are associated with mitochondrial dysfunction and frequently linked to human cancer
Summary
Large-scale exome/genome sequencing studies have recently revealed that recurrent mutations in the SPOP gene occur in up to 15% of prostate cancers [1,2,3,4]. The SPOP mutant subset of prostate cancers had some notable molecular features, including mutual exclusivity with ERG gene rearrangement, elevated levels of DNA methylation, homogeneous gene expression patterns, frequent deletion of CHD1 and overexpression of SPINK1 mRNA, supporting the concept that SPOP mutation tumors represent a distinct molecular subclass of prostate cancer [4] SPOP is one of the adaptor proteins of the CUL3-RBX1 E3 ubiquitin ligase complexes. It selectively recruits substrates via its N-terminal MATH domain, whereas its BTB and BACK domains mediate oligomerization and interaction with CUL3 [5]. Limited numbers of SPOP substrates have been identified and functionally explored
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