1. Academic Validation
  2. TRIB3 destabilizes tumor suppressor PPARα expression through ubiquitin-mediated proteasome degradation in acute myeloid leukemia

TRIB3 destabilizes tumor suppressor PPARα expression through ubiquitin-mediated proteasome degradation in acute myeloid leukemia

  • Life Sci. 2020 Sep 15;257:118021. doi: 10.1016/j.lfs.2020.118021.
Xu Luo 1 Liang Zhong 2 Lihua Yu 3 Ling Xiong 4 Wenran Dan 4 Jian Li 2 Jiao Ye 2 Xuan Chu 4 Chen Liu 2 Beizhong Liu 5
Affiliations

Affiliations

  • 1 Central Laboratory of Yongchuan Hospital, Chongqing Medical University, Chongqing 402160, China; Key Laboratory of Laboratory Medical Diagnostics, Ministry of Education, Department of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China.
  • 2 Key Laboratory of Laboratory Medical Diagnostics, Ministry of Education, Department of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China.
  • 3 Clinical Laboratory of Yongchuan Hospital, Chongqing Medical University, Chongqing 402160, China.
  • 4 Central Laboratory of Yongchuan Hospital, Chongqing Medical University, Chongqing 402160, China.
  • 5 Central Laboratory of Yongchuan Hospital, Chongqing Medical University, Chongqing 402160, China; Key Laboratory of Laboratory Medical Diagnostics, Ministry of Education, Department of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China. Electronic address: [email protected].
Abstract

Aims: Tribbles homolog 3 (TRIB3) is emerging as a multifunctional oncoprotein associated with various cellular events in different tumors. However, the regulatory mechanism of TRIB3 in acute myeloid leukemia (AML) remains unknown. This study aims to investigate the molecular mechanisms and uncover the functions of TRIB3 in AML.

Methods: Western blotting and quantitative Real-Time PCR were used to analyze the expression levels of TRIB3, Peroxisome Proliferator-activated Receptor α (PPARα), Apoptosis markers and Autophagy markers in AML cells. Flow cytometry was used to assess cell Apoptosis. The interaction of TRIB3 and PPARα was evaluated by immunofluorescence, coimmunoprecipitation, and in vivo ubiquitination assays.

Key findings: We demonstrated that downregulating TRIB3 in leukemic cells effectively induced Apoptosis and Autophagy by regulating the degradation of PPARα. Mechanistically, TRIB3 interacted with PPARα and contributed to its destabilization by promoting its ubiquitination. When PPARα was activated by its specific agonist clofibrate, the Apoptosis and Autophagy of AML cells were significantly enhanced. These results were confirmed by rescue experiments. Blocking PPARα expression using the PPARα Inhibitor GW6471 reversed the functional influence of TRIB3 on AML cells.

Significance: The aim of this study is to provide evidence of the degradation of PPARα by TRIB3 via ubiquitin-dependent proteasomal degradation. This process meditates the progression of AML and prolongs the survival of leukemic cells. As a result, these data indicate that TRIB3 is a novel and promising therapeutic target for AML treatment.

Keywords

Acute myeloid leukemia; Apoptosis; Autophagy; Degradation; Peroxisome proliferator-activated receptor α; Proteasome; Tribbles homolog 3.

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