title: SMAD4 suppresses AURKA-induced metastatic phenotypes via degradation of AURKA in a TGFβ-independent manner.
abstract: SMAD4 has been suggested to inhibit the activity of the WNT/β-catenin signaling pathway in cancer. However, the mechanism by which SMAD4 antagonizes WNT/β-catenin signaling in cancer remains largely unknown. Aurora A kinase (AURKA), which is frequently overexpressed in cancer, increases the transcriptional activity of β-catenin/T-cell factor (TCF) complex by stabilizing β-catenin through the inhibition of GSK-3β. Here, SMAD4 modulated AURKA in a TGFβ-independent manner. Overexpression of SMAD4 significantly suppressed AURKA function, including colony formation, migration, and invasion of cell lines. In addition, SMAD4 bound to AURKA induced degradation of AURKA by the proteasome. A luciferase activity assay revealed that the transcriptional activity of the β-catenin/TCF complex was elevated by AURKA, but decreased by SMAD4 overexpression. Moreover, target gene analysis showed that SMAD4 abrogated the AURKA-mediated increase of β-catenin target genes. However, this inhibitory effect of SMAD4 was abolished by overexpression of AURKA or silencing of AURKA in SMAD4-overexpressed cells. Meanwhile, the SMAD4-mediated repression of AURKA and β-catenin was independent of TGFβ signaling because blockage of TGFβR1 or restoration of TGFβ signaling did not prevent suppression of AURKA and β-catenin signaling by SMAD4. These results indicate that the tumor-suppressive function of SMAD4 is mediated by downregulation of β-catenin transcriptional activity via AURKA degradation in a TGFβ-independent manner.
  
  
  CONCLUSIONS
  SMAD4 interacts with AURKA and antagonizes its tumor-promoting potential, thus demonstrating a novel mechanism of tumor suppression.
authors: Department of Pharmacology, School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China.
authors: Lina
authors: L
authors: Jia
authors: Research Institute of Pharmaceutical Science, Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul, Korea.
authors: Hun Seok
authors: HS
authors: Lee
authors: Department of Pharmacology, School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China.
authors: Chun Fu
authors: CF
authors: Wu
authors: College of Pharmacy, Keimyung University, Deagu, Korea.
authors: Juthika
authors: J
authors: Kundu
authors: Department of Pharmacy, College of Pharmacy, Ajou University, Gyuggido, Korea.
authors: Sang Gyu
authors: SG
authors: Park
authors: Research Institute of Pharmaceutical Science, Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul, Korea. Tumor Microenvironment Global Core Research Center, Seoul National University, Seoul, Korea.
authors: Ryong Nam
authors: RN
authors: Kim
authors: Department of Pharmacology, School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China.
authors: Li-Hui
authors: LH
authors: Wang
authors: Department of Bioengineering, Faculty of Engineering, Adana Science and Technology, Adana, Turkey.
authors: Özgür Cem
authors: ÖC
authors: Erkin
authors: Institutes of Entrepreneurial BioConvergence, Seoul National University, Seoul, Korea.
authors: Jong-Sun
authors: JS
authors: Choi
authors: Department of Pathology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors: Seoung Wan
authors: SW
authors: Chae
authors: Research Institute of Pharmaceutical Science, Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul, Korea.
authors: Ho Bin
authors: HB
authors: Yang
authors: Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors: Yoon-La
authors: YL
authors: Choi
authors: Research Institute of Pharmaceutical Science, Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul, Korea. Tumor Microenvironment Global Core Research Center, Seoul National University, Seoul, Korea. Institutes of Entrepreneurial BioConvergence, Seoul National University, Seoul, Korea. ykeeshin@snu.ac.kr.
authors: Young Kee
authors: YK
authors: Shin
mesh_terms: D000818:Animals; D064096:Aurora Kinase A / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D009154:Mutation; D041681:NIH 3T3 Cells; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D015398:Signal Transduction; D051901:Smad4 Protein / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: C495270:CTNNB1 protein, human; C497796:SMAD4 protein, human; D051901:Smad4 Protein; D016212:Transforming Growth Factor beta; D051176:beta Catenin; C576917:AURKA protein, human; D064096:Aurora Kinase A; D046988:Proteasome Endopeptidase Complex