Signal peptide peptidase promotes tumor progression via facilitating FKBP8 degradation

Fu Fei Hsu, Yi Tai Chou, Ming Tsai Chiang, Fu An Li, Chi Tai Yeh, Wei Hwa Lee, Lee Young Chau

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2 Citations (Scopus)

Abstract

Signal peptide peptidase (SPP) is an endoplasmic reticulum (ER)-resident aspartyl protease mediating intramembrane cleavage of type II transmembrane proteins. Increasing evidence has supported the role of SPP in ER-associated protein degradation. In the present study, we show that SPP expression is highly induced in human lung and breast cancers and correlated with disease outcome. Stable depletion of SPP expression in lung and breast cancer cell lines significantly reduced cell growth and migration/invasion abilities. Quantitative analysis of the proteomic changes of microsomal proteins in lung cancer cells by the stable isotope labeling with amino acids in cell culture (SILAC) approach revealed that the level of FKBP8, an endogenous inhibitor of mTOR, was significantly increased following SPP depletion. Co-immunoprecipitation assay and confocal immunofluorescence demonstrated that SPP interacted and colocalized with FKBP8 in ER, supporting that FKBP8 is a protein substrate of SPP. Cycloheximide chase and proteasome inhibition experiments revealed that SPP-mediated proteolysis facilitated FKBP8 protein degradation in cytosol. Further experiment demonstrated that the levels of phosphorylation in mTOR and its downstream effectors, S6K and 4E-BP1, were significantly lower in SPP-depleted cells. The reduced mTOR signaling and decreases of growth and migration/invasion abilities induced by SPP depletion in cancer cells could be reversed by FKBP8 downregulation. The implication of FKBP8 in SPP-mediated tumorigenicity was also observed in the xenograft model. Together, these findings disclose that SPP promotes tumor progression, at least in part, via facilitating the degradation of FKBP8 to enhance mTOR signaling.

Original languageEnglish
JournalOncogene
DOIs
Publication statusAccepted/In press - Jan 1 2018

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ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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