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The FBXW2-MSX2-SOX2 axis regulates stem cell property and drug resistance of cancer cells.
Yin, Yuan; Xie, Chuan-Ming; Li, Hua; Tan, Mingjia; Chen, Guoan; Schiff, Rachel; Xiong, Xiufang; Sun, Yi.
Afiliação
  • Yin Y; Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109.
  • Xie CM; Wuxi Cancer Institute, Affiliated Hospital of Jiangnan University, Wuxi 214062, China.
  • Li H; Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109.
  • Tan M; Institute of Hepatobiliary Surgery, Southwest Hospital, The Third Military Medical University (Army Medical University), Chongqing, 400038, China.
  • Chen G; Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109.
  • Schiff R; Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109.
  • Xiong X; School of Medicine, Southern University of Science and Technology, Shenzhen 518055, Guangdong, China.
  • Sun Y; Lester and Sue Smith Breast Center, Department of Medicine, Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030.
Proc Natl Acad Sci U S A ; 116(41): 20528-20538, 2019 10 08.
Article em En | MEDLINE | ID: mdl-31548378
SOX2 is a key transcription factor that plays critical roles in maintaining stem cell property and conferring drug resistance. However, the underlying mechanisms by which SOX2 level is precisely regulated remain elusive. Here we report that MLN4924, also known as pevonedistat, a small-molecule inhibitor of neddylation currently in phase II clinical trials, down-regulates SOX2 expression via causing accumulation of MSX2, a known transcription repressor of SOX2 expression. Mechanistic characterization revealed that MSX2 is a substrate of FBXW2 E3 ligase. FBXW2 binds to MSX2 and promotes MSX2 ubiquitylation and degradation. Likewise, FBXW2 overexpression shortens the protein half-life of MSX2, whereas FBXW2 knockdown extends it. We further identified hypoxia as a stress condition that induces VRK2 kinase to facilitate MSX2-FBXW2 binding and FBXW2-mediated MSX2 ubiquitylation and degradation, leading to SOX2 induction via derepression. Biologically, expression of FBXW2 or SOX2 promotes tumor sphere formation, which is blocked by MSX2 expression. By down-regulating SOX2 through inactivation of FBXW2 E3 ligase, MLN4924 sensitizes breast cancer cells to tamoxifen in both in vitro and in vivo cancer cell models. Thus, a negative cascade of the FBXW2-MSX2-SOX2 axis was established, which regulates stem cell property and drug resistance. Finally, an inverse correlation of expression was found between FBXW2 and MSX2 in lung and breast cancer tissues. Collectively, our study revealed an anticancer mechanism of MLN4924. By inactivating FBXW2, MLN4924 caused MSX2 accumulation to repress SOX2 expression, leading to suppression of stem cell property and sensitization of breast cancer cells to tamoxifen.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Células-Tronco Neoplásicas / Proteínas de Homeodomínio / Resistencia a Medicamentos Antineoplásicos / Proteínas F-Box / Fatores de Transcrição SOXB1 / Neoplasias Pulmonares Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2019 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Células-Tronco Neoplásicas / Proteínas de Homeodomínio / Resistencia a Medicamentos Antineoplásicos / Proteínas F-Box / Fatores de Transcrição SOXB1 / Neoplasias Pulmonares Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2019 Tipo de documento: Article