1. Academic Validation
  2. TRIM28 represses renal cell carcinoma cell proliferation by inhibiting TFE3/KDM6A-regulated autophagy

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

  • J Biol Chem. 2023 Mar 17;104621. doi: 10.1016/j.jbc.2023.104621.
Tanjing Song 1 Suli Lv 2 Xianyun Ma 2 Xuefeng Zhao 2 Li Fan 3 Qingli Zou 2 Neng Li 2 Yingying Yan 2 Wen Zhang 3 Lidong Sun 4
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology,13 Hangkong Road, Wuhan, China 430030; Cell Architecture Research Institute, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
  • 2 Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology,13 Hangkong Road, Wuhan, China 430030.
  • 3 Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan,China.
  • 4 Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology,13 Hangkong Road, Wuhan, China 430030; Cell Architecture Research Institute, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China. Electronic address: LidongSun@hust.edu.cn.
Abstract

Autophagy plays a pivotal role in physiology and pathophysiology, including Cancer. Mechanisms of Autophagy dysregulation in Cancer remain elusive. Loss-of-function of TRIM28, a multi-function protein, is seen in familial kidney malignancy, but the mechanism by which TRIM28 contributes to the etiology of kidney malignancy is unclear. In this study, we show TRIM28 retards kidney Cancer cell proliferation through inhibiting Autophagy. Mechanistically, we find TRIM28 promotes ubiquitination and proteasome-mediated degradation of transcription factor TFE3, which is critical for autophagic gene expression. Genetic activation of TFE3 due to gene fusion is known to cause human kidney malignancy, but whether and how transcription activation by TFE3 involves chromatin changes is unclear. Here, we find another mode of TFE3 activation in human renal carcinoma. We find that TFE3 is constitutively localized to the cell nucleus in human and mouse kidney Cancer, where it increases autophagic gene expression and promotes cell Autophagy as well as proliferation. We further uncover that TFE3 interacts with and recruits histone H3K27 demethylase KDM6A for autophagic gene upregulation. We reveal that KDM6A contributes to expression of TFE3 target genes through increasing H3K4me3 rather than demethylating H3K27. Collectively, in this study, we identify a functional TRIM28-TFE3-KDM6A signal axis which plays a critical role in kidney Cancer cell Autophagy and proliferation.

Keywords

KDM6A; TFE3; TRIM28; autophagy; histone methylation; kidney cancer; ubiquitination.

Figures
Products
Inhibitors & Agonists
Other Products