title: Metadherin/Astrocyte elevated gene-1 positively regulates the stability and function of forkhead box M1 during tumorigenesis.
abstract: Forkhead box M1 (FOXM1) is overexpressed and activates numerous oncoproteins in tumors. However, the mechanism by which the FOXM1 protein aberrantly accumulates in human cancer remains uncertain. This study was designed to clarify the upstream signaling pathway(s) that regulate FOXM1 protein stability and transcriptional activity.
  
  
  
  Mass spectrometry and immunoprecipitation were performed to identify the FOXM-metadherin (MTDH) interaction. In vivo and in vitro ubiquitination assays were conducted to test the effect of MTDH on FOXM1 stability. Chromatin immunoprecipitation assays were used to determine the involvement of MTDH in FOXM1 transcriptional activity. Cell invasion assays, tube formation assays, and in vivo tumor formation assays were performed to evaluate the cooperative activities of FOXM1 and MTDH during tumorigenesis.
  
  
  
  MTDH directly interacts with FOXM1 via the N-terminal inhibitory domain of MTDH, and this interaction disrupted the binding of cadherin-1 to FOXM1, thus protecting FOXM1 from subsequent proteasomal degradation. Deleting the MTDH-binding sites of FOXM1 abolished the MTDH overexpression-mediated stabilization of FOXM1. MTDH also bound to FOXM1 target gene promoters and enhanced FOXM1 transcriptional activity. MTDH knockdown destabilized FOXM1 and attenuated its transcriptional activity, consequently inhibiting cell cycle progression, angiogenesis, and cancer cell invasion in vitro and in vivo; these effects were abolished via forced overexpression of a stabilized mutant form of FOXM1. Thus, MTDH stabilized FOXM1 and supported the sustained activation of FOXM1 target genes.
  
  
  
  These findings highlight a novel MTDH-regulated mechanism of FOXM1 stabilization and provide profound insight into the tumorigenic events simultaneously mediated by FOXM1 and MTDH.
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China.
authors.forename: Lixuan
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China.
authors.forename: Kejun
authors.initials: K
authors.lastname: He
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Yan
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China.
authors.forename: Yibing
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China.
authors.forename: Xinya
authors.initials: X
authors.lastname: Gao
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China.
authors.forename: Maolei
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China.
authors.forename: Zhibo
authors.initials: Z
authors.lastname: Xia
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China.
authors.forename: Zhengsong
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.|Program in Cancer Biology, The University of Texas Graduate School of Biomedical Sciences, Houston, Texas, USA.
authors.forename: Suyun
authors.initials: S
authors.lastname: Huang
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China.
authors.forename: Nu
authors.initials: N
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology*; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000072278:Forkhead Box Protein M1 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008565:Membrane Proteins; D051379:Mice; D055550:Protein Stability; D016601:RNA-Binding Proteins; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D054875:Ubiquitination; D023041:Xenograft Model Antitumor Assays
chemical_list: D015820:Cadherins; D015815:Cell Adhesion Molecules; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; C483039:MTDH protein, human; D008565:Membrane Proteins; D016601:RNA-Binding Proteins
keywords: FOXM1; MTDH; transcription; tumorigenesis; ubiquitination