title: Cytoplasmic Metadherin (MTDH) provides survival advantage under conditions of stress by acting as RNA-binding protein.
abstract: Overexpression of metadherin (MTDH) has been documented in many solid tumors and is implicated in metastasis and chemoresistance. MTDH has been detected at the plasma membrane as well as in the cytoplasm and nucleus, and the function of MTDH in these locales remains under investigation. In the nucleus, MTDH acts as a transcription co-factor to induce expression of chemoresistance-associated genes. However, MTDH is predominantly cytoplasmic in prostate tumors, and this localization correlates with poor prognosis. Herein, we used endometrial cancer cells as a model system to define a new role for MTDH in the cytoplasm. First, MTDH was primarily localized to the cytoplasm in endometrial cancer cells, and the N-terminal region of MTDH was required to maintain cytoplasmic localization. Next, we identified novel binding partners for cytoplasmic MTDH, including RNA-binding proteins and components of the RNA-induced silencing complex. Nucleic acids were required for the association of MTDH with these cytoplasmic proteins. Furthermore, MTDH interacted with and regulated protein expression of multiple mRNAs, such as PDCD10 and KDM6A. Depletion of cytoplasmic MTDH was associated with increased stress granule formation, reduced survival in response to chemotherapy and the tyrosine kinase inhibitor BIBF1120, Rad51 nuclear accumulation, and cell cycle arrest at G(2)/M. Finally, in vivo tumor formation was abrogated with knockdown of cytoplasmic MTDH. Taken together, our data identify a novel function for cytoplasmic MTDH as an RNA-binding protein. Our findings implicate cytoplasmic MTDH in cell survival and broad drug resistance via association with RNA and RNA-binding proteins.
authors.affiliation: Department of Obstetrics and Gynecology, The University of Iowa, Iowa City, Iowa 52242, USA. xiangbing-meng@uiowa.edu
authors.forename: Xiangbing
authors.initials: X
authors.lastname: Meng
authors.forename: Danlin
authors.initials: D
authors.lastname: Zhu
authors.forename: Shujie
authors.initials: S
authors.lastname: Yang
authors.forename: Xinjun
authors.initials: X
authors.lastname: Wang
authors.forename: Zhi
authors.initials: Z
authors.lastname: Xiong
authors.forename: Yuping
authors.initials: Y
authors.lastname: Zhang
authors.forename: Pavla
authors.initials: P
authors.lastname: Brachova
authors.forename: Kimberly K
authors.initials: KK
authors.lastname: Leslie
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival / Q000502:physiology; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D005260:Female; D056466:Histone Demethylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008819:Mice, Nude; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D014176:Protein Biosynthesis / Q000502:physiology*; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D017384:Sequence Deletion; D013312:Stress, Physiological / Q000502:physiology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D015815:Cell Adhesion Molecules; C483039:MTDH protein, human; D008565:Membrane Proteins; D009687:Nuclear Proteins; C495390:PDCD10 protein, human; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D056466:Histone Demethylases; C523998:KDM6A protein, human