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DTL promotes cancer progression by PDCD4 ubiquitin-dependent degradation

Haoran Cui1, Qin Wang2, Zhenchuan Lei3

  • 1Department of Cell Biology and Key Laboratory of Experimental Teratology, Ministry of Education, Shandong University School of Medicine, Jinan, Shandong, China.

Journal of Experimental & Clinical Cancer Research : CR
|August 15, 2019
PubMed
Abstract

Insights

The study reveals that DTL degrades the tumor suppressor PDCD4 (Programmed cell death 4), promoting cancer cell proliferation and migration. This finding highlights DTL as a potential therapeutic target in cancer development.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • The ubiquitin E3 ligase CUL4A is implicated in cancer development.
  • DTL, a CUL4-DDB1 associated factor (DCAF), may play a role in oncogenesis.
  • Programmed cell death 4 (PDCD4) is a tumor suppressor involved in apoptosis and tumor progression.

Purpose of the Study:

  • To investigate the role of DTL in cancer development.
  • To identify PDCD4 as a potential substrate of DTL.
  • To elucidate the mechanism by which DTL influences cancer cell behavior.

Main Methods:

  • Affinity-purification mass spectrometry and Co-immunoprecipitation (Co-IP) to identify and verify protein interactions.
  • Quantitative real-time PCR to assess mRNA levels.
  • Lentivirus-mediated gene manipulation (overexpression and knockdown) to study gene function.
  • In vitro ubiquitination assays to determine degradation mechanisms.
  • Transwell, wound healing, Matrigel, MTT, and colony formation assays to evaluate cell migration, invasion, and proliferation.
  • Tumorigenesis assays in nude mice.

Main Results:

  • PDCD4 was identified as a substrate of DTL, with DTL accelerating PDCD4 degradation via ubiquitination.
  • DTL overexpression decreased PDCD4 protein levels and enhanced cancer cell proliferation, migration, and invasion.
  • DTL was significantly upregulated in cancer tissues, correlating with lower patient survival rates.
  • Silencing PDCD4 reversed the DTL-induced cancer cell phenotypes.

Conclusions:

  • DTL promotes cancer development by degrading the tumor suppressor PDCD4.
  • DTL enhances cancer cell motility and proliferation.
  • DTL represents a potential therapeutic target for cancer treatment.
Keywords:
CUL4ACancer developmentDTLPDCD4

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