Cancer Communications (Aug 2021)

Mitochondrial transcription factor A plays opposite roles in the initiation and progression of colitis‐associated cancer

  • Shirong Yang,
  • Xianli He,
  • Jing Zhao,
  • Dalin Wang,
  • Shanshan Guo,
  • Tian Gao,
  • Gang Wang,
  • Chao Jin,
  • Zeyu Yan,
  • Nan Wang,
  • Yongxing Wang,
  • Yilin Zhao,
  • Jinliang Xing,
  • Qichao Huang

DOI
https://doi.org/10.1002/cac2.12184
Journal volume & issue
Vol. 41, no. 8
pp. 695 – 714

Abstract

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Abstract Background Mitochondria are key regulators in cell proliferation and apoptosis. Alterations in mitochondrial function are closely associated with inflammation and tumorigenesis. This study aimed to investigate whether mitochondrial transcription factor A (TFAM), a key regulator of mitochondrial DNA transcription and replication, is involved in the initiation and progression of colitis‐associated cancer (CAC). Methods TFAM expression was examined in tissue samples of inflammatory bowel diseases (IBD) and CAC by immunohistochemistry. Intestinal epithelial cell (IEC)‐specific TFAM‐knockout mice (TFAM△IEC) and colorectal cancer (CRC) cells with TFAM knockdown or overexpression were used to evaluate the role of TFAM in colitis and the initiation and progression of CAC. The underlying mechanisms of TFAM were also explored by analyzing mitochondrial respiration function and biogenesis. Results The expression of TFAM was downregulated in active IBD and negatively associated with the disease activity. The downregulation of TFAM in IECs was induced by interleukin‐6 in a signal transducer and activator of transcription 3 (STAT3)/miR‐23b‐dependent manner. In addition, TFAM knockout impaired IEC turnover to promote dextran sulfate sodium (DSS)‐induced colitis in mice. Of note, TFAM knockout increased the susceptibility of mice to azoxymethane/DSS‐induced CAC and TFAM overexpression protected mice from intestinal inflammation and colitis‐associated tumorigenesis. By contrast, TFAM expression was upregulated in CAC tissues and contributed to cell growth. Furthermore, it was demonstrated that β‐catenin induced the upregulation of TFAM through c‐Myc in CRC cells. Mechanistically, TFAM promoted the proliferation of both IECs and CRC cells by increasing mitochondrial biogenesis and activity. Conclusions TFAM plays a dual role in the initiation and progression of CAC, providing a novel understanding of CAC pathogenesis.

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