title: Post-transcriptional repression of FOXO1 by QKI results in low levels of FOXO1 expression in breast cancer cells.
abstract: The RNA-binding protein Quaking (QKI) is known to be essential for embryonic development and postnatal myelination. Forkhead box O1 (FOXO1) is a critical tumor suppressor for cell proliferation control. Dysregulation of FOXO1 expression has been observed in a variety of cancers. In the present study, we demonstrated that QKI decreased FOXO1 mRNA expression at the post-transcriptional level. QKI was able to bind the 3'UTR of FOXO1 mRNA directly and decreased its mRNA stability. To determine whether QKI-mediated post-transcriptional repression of FOXO1 indeed plays a role in cancer cells, we first detected both QKI and FOXO1 expression in four breast cancer cell lines. FOXO1 expression was extremely low in these cell lines, whereas QKI expression was relative high. Knockdown of QKI significantly restored FOXO1 expression. ATRA, an inducer of apoptosis or differentiation, dramatically enhanced FOXO1 expression while it repressed QKI expression. Importantly, the ATRA-induced increase in FOXO1 expression was dependent on QKI-mediated post-transcriptional regulation. Consistently, 5-FU, a widely used chemotherapeutic agent, increased FOXO1 expression via inhibition of QKI. In summary, our study provides initial evidence demonstrating that QKI-mediated repression of FOXO1 may be one of the factors contributing to the oncogenesis and progression of breast carcinoma, which suggests that targeting QKI may serve as a novel strategy to sensitize breast cancers to chemotherapy.
authors.affiliation: Department of Biochemistry and Molecular Biology, The State Key Laboratory of Cancer Biology, The Fourth Military Medical University, Xi'an 710032, P.R. China.
authors.forename: Fang
authors.initials: F
authors.lastname: Yu
authors.affiliation: Department of Biochemistry and Molecular Biology, The State Key Laboratory of Cancer Biology, The Fourth Military Medical University, Xi'an 710032, P.R. China.
authors.forename: Liang
authors.initials: L
authors.lastname: Jin
authors.affiliation: Department of Biochemistry and Molecular Biology, The State Key Laboratory of Cancer Biology, The Fourth Military Medical University, Xi'an 710032, P.R. China.
authors.forename: Guodong
authors.initials: G
authors.lastname: Yang
authors.affiliation: Department of Toxicology, The Fourth Military Medical University, Xi'an 710032, P.R. China.
authors.forename: Lin
authors.initials: L
authors.lastname: Ji
authors.affiliation: Department of Nutrition and Food Hygiene, The Fourth Military Medical University, Xi'an 710032, P.R. China.
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Biochemistry and Molecular Biology, The State Key Laboratory of Cancer Biology, The Fourth Military Medical University, Xi'an 710032, P.R. China.
authors.forename: Zifan
authors.initials: Z
authors.lastname: Lu
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001943:Breast Neoplasms; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D061986:MCF-7 Cells; D020871:RNA Stability; D016601:RNA-Binding Proteins / Q000502:physiology*; D014158:Transcription, Genetic; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D000964:Antimetabolites, Antineoplastic; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C490832:QKI protein, human; D016601:RNA-Binding Proteins; D014212:Tretinoin; D005472:Fluorouracil