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TRIM28 represses renal cell carcinoma cell proliferation by inhibiting TFE3/KDM6A-regulated autophagy

Tanjing Song1, Suli Lv2, Xianyun Ma2

  • 1Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Cell Architecture Research Institute, Huazhong University of Science and Technology, Wuhan, Hubei, China.

The Journal of Biological Chemistry
|March 19, 2023
PubMed

Insights

The TRIM28-TFE3-KDM6A pathway regulates kidney cancer cell growth by controlling autophagy. TRIM28 inhibits TFE3, a key factor in autophagic gene expression, thus slowing cancer proliferation.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Autophagy is crucial in cancer, but its dysregulation mechanisms are unclear.
  • TRIM28 loss is linked to kidney cancer, yet its role is not fully understood.
  • TFE3 gene fusions cause kidney cancer, but TFE3's broader role in chromatin regulation needs clarification.

Purpose of the Study:

  • To elucidate the mechanism by which TRIM28 influences kidney cancer.
  • To investigate the role of TFE3 and KDM6A in kidney cancer cell proliferation and autophagy.
  • To identify key signaling pathways regulating kidney cancer progression.

Main Methods:

  • Investigated TRIM28's effect on autophagy and kidney cancer cell proliferation.
  • Analyzed TRIM28-mediated ubiquitination and degradation of TFE3.
  • Examined TFE3 nuclear localization and its interaction with KDM6A in kidney cancer cells.
  • Assessed the impact of KDM6A on histone modifications and gene expression.

Main Results:

  • TRIM28 inhibits kidney cancer cell proliferation by suppressing autophagy.
  • TRIM28 promotes TFE3 degradation, a transcription factor essential for autophagic gene expression.
  • TFE3 is constitutively nuclear in kidney cancer, upregulating autophagic genes and promoting proliferation.
  • TFE3 recruits KDM6A to enhance autophagic gene expression via H3K4me3 modification, not H3K27 demethylation.

Conclusions:

  • Identified a TRIM28-TFE3-KDM6A signaling axis critical for kidney cancer.
  • TRIM28 acts as a tumor suppressor by inhibiting autophagy through TFE3 degradation.
  • TFE3 and KDM6A promote kidney cancer cell autophagy and proliferation via epigenetic modifications.
Keywords:
KDM6ATFE3TRIM28autophagyhistone methylationkidney cancerubiquitination

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