1. Academic Validation
  2. Activation of the clock gene TIMELESS by H3k27 acetylation promotes colorectal cancer tumorigenesis by binding to Myosin-9

Activation of the clock gene TIMELESS by H3k27 acetylation promotes colorectal cancer tumorigenesis by binding to Myosin-9

  • J Exp Clin Cancer Res. 2021 May 10;40(1):162. doi: 10.1186/s13046-021-01936-4.
Meng Cao  # 1 Yi Wang  # 2 Yijing Xiao  # 3 Dandan Zheng 2 Chunchun Zhi 4 Xin Xia 2 Xiaoqin Yuan 5 6
Affiliations

Affiliations

  • 1 Department of General Surgery, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, China.
  • 2 Department of Anatomy, Histology and Embryology, Nanjing Medical University, Xuehai Building, Rm D509, 101 Longmian Avenue, Jiangning District, Nanjing, 211166, China.
  • 3 Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, 210029, China.
  • 4 Department of Pathology, Nanjing Jinling Hospital, Nanjing University School of Medicine, Nanjing, 210002, China.
  • 5 Department of Anatomy, Histology and Embryology, Nanjing Medical University, Xuehai Building, Rm D509, 101 Longmian Avenue, Jiangning District, Nanjing, 211166, China. yuanxq@njmu.edu.cn.
  • 6 Key Laboratory for Aging & Disease, Nanjing Medical University, Nanjing, 211166, China. yuanxq@njmu.edu.cn.
  • # Contributed equally.
Abstract

Background: Colorectal Cancer (CRC) is a common tumor characterized by its high mortality. However, the underlying molecular mechanisms that drive CRC tumorigenesis are unclear. Clock genes have important roles in tumor development. In the present study, the expression and functions of clock gene TIMELESS (encoding the Timeless protein) in CRC were investigated.

Methods: Immunohistochemistry, cell proliferation, migration, invasion, EMT and xenograft tumor experiments were used to prove the function of Timeless in the tumorigenesis of CRC. Immunoprecipitation, mass spectrometry, Immunofluorescence and Chromatin immunoprecipitation (ChIP) were utilized to clarify the mechanism of Timeless in regulating CRC tumorigenesis.

Results: We found that Timeless was upregulated in CRC tissues compared with corresponding normal tissues and its expression was closely associated with the TNM stages and overall survival of CRC patients. Functional studies demonstrated that Timeless promoted the proliferation, invasion, and EMT of CRC cells in vitro and in vivo. Mechanistic investigations showed that Timeless activated the β-catenin signal pathway by binding to Myosin-9, which binds to β-catenin to induce its nuclear translocation. The upregulation of Timeless was attributed to CREB-binding protein (CBP)/p300-mediated H3K27 acetylation of the promoter region of Timeless.

Conclusion: Timeless regulates the tumorigenesis of CRC by binding to and regulating myosin-9, suggesting Timeless might be a potential prognostic biomarker and therapeutic target for CRC.

Keywords

Colorectal cancer; Myosin-9; Timeless; Wnt/β-catenin pathway.

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