Dysregulation of INF2-mediated mitochondrial fission in SPOP-mutated prostate cancer

Xiaofeng Jin, Jie Wang, Kun Gao, Pingzhao Zhang, Longfang Yao, Yan Tang, Lisha Tang, Jian Ma, Jiantao Xiao, Enceng Zhang, Jie Zhu, Bin Zhang, Shi Min Zhao, Yao Li, Shancheng Ren, Haojie Huang, Long Yu, Chenji Wang

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article numbere1006748
JournalPLoS Genetics
Volume13
Issue number4
DOIs
StatePublished - Apr 1 2017

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Mitochondrial Dynamics
speckle
prostatic neoplasms
cancer
Prostatic Neoplasms
protein
Proteins
proteins
Ubiquitination
mitochondrion
Mitochondria
mitochondria
mutation
Exome
Mutation
Ubiquitin-Protein Ligases
protein isoforms
mutants
ubiquitin-protein ligase
cell invasion

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

Jin, X., Wang, J., Gao, K., Zhang, P., Yao, L., Tang, Y., ... Wang, C. (2017). Dysregulation of INF2-mediated mitochondrial fission in SPOP-mutated prostate cancer. PLoS Genetics, 13(4), [e1006748]. https://doi.org/10.1371/journal.pgen.1006748

Dysregulation of INF2-mediated mitochondrial fission in SPOP-mutated prostate cancer. / Jin, Xiaofeng; Wang, Jie; Gao, Kun; Zhang, Pingzhao; Yao, Longfang; Tang, Yan; Tang, Lisha; Ma, Jian; Xiao, Jiantao; Zhang, Enceng; Zhu, Jie; Zhang, Bin; Zhao, Shi Min; Li, Yao; Ren, Shancheng; Huang, Haojie; Yu, Long; Wang, Chenji.

In: PLoS Genetics, Vol. 13, No. 4, e1006748, 01.04.2017.

Research output: Contribution to journalArticle

Jin, X, Wang, J, Gao, K, Zhang, P, Yao, L, Tang, Y, Tang, L, Ma, J, Xiao, J, Zhang, E, Zhu, J, Zhang, B, Zhao, SM, Li, Y, Ren, S, Huang, H, Yu, L & Wang, C 2017, 'Dysregulation of INF2-mediated mitochondrial fission in SPOP-mutated prostate cancer', PLoS Genetics, vol. 13, no. 4, e1006748. https://doi.org/10.1371/journal.pgen.1006748
Jin, Xiaofeng ; Wang, Jie ; Gao, Kun ; Zhang, Pingzhao ; Yao, Longfang ; Tang, Yan ; Tang, Lisha ; Ma, Jian ; Xiao, Jiantao ; Zhang, Enceng ; Zhu, Jie ; Zhang, Bin ; Zhao, Shi Min ; Li, Yao ; Ren, Shancheng ; Huang, Haojie ; Yu, Long ; Wang, Chenji. / Dysregulation of INF2-mediated mitochondrial fission in SPOP-mutated prostate cancer. In: PLoS Genetics. 2017 ; Vol. 13, No. 4.
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