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Dysregulation of the miR-194-CUL4B negative feedback loop drives tumorigenesis in non-small-cell lung carcinoma

Jun Mi1,2, Yongxin Zou1, Xiaohua Lin1

  • 1The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Molecular Medicine and Genetics, Shandong University School of Basic Medical Sciences, Jinan, China.

Molecular Oncology
|February 7, 2017
PubMed

Insights

MicroRNA-194 (miR-194) suppresses non-small cell lung cancer (NSCLC) by targeting Cullin 4B (CUL4B). A feedback loop between miR-194 and CRL4B contributes to lung tumorigenesis, offering therapeutic potential.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Cullin 4B (CUL4B) is overexpressed in cancers, repressing tumor suppressors via epigenetic mechanisms.
  • Mechanisms of CUL4B upregulation are not fully understood.
  • CUL4B is a scaffold protein assembling CRL4B ubiquitin ligase complexes.

Purpose of the Study:

  • Investigate CUL4B upregulation in non-small cell lung carcinoma (NSCLC).
  • Elucidate the regulatory relationship between miR-194 and CUL4B in NSCLC.
  • Determine the role of the miR-194/CUL4B axis in lung cancer progression.

Main Methods:

  • Correlation analysis of miR-194 and CUL4B in NSCLC tissues.
  • Luciferase reporter assays to confirm direct targeting of CUL4B 3'-UTR by miR-194.
  • In vitro and in vivo assays to assess CUL4B's role in NSCLC proliferation, migration, and tumor formation.
  • Chromatin immunoprecipitation (ChIP) assays to investigate CRL4B-mediated epigenetic repression of miR-194.

Main Results:

  • CUL4B is upregulated in NSCLC and promotes proliferation, migration, and tumor growth.
  • miR-194 directly targets and downregulates CUL4B, with an inverse correlation observed in patient samples.
  • CRL4B epigenetically represses miR-194 via H2AK119 monoubiquitination and H3K27 trimethylation, establishing a double-negative feedback loop.
  • RBX1, a CRL4B component, is also targeted by miR-194.

Conclusions:

  • A feedback loop between miR-194 and CRL4B, involving epigenetic regulation, is dysregulated in NSCLC.
  • miR-194 acts as a tumor suppressor by downregulating CUL4B.
  • Targeting the miR-194/CUL4B axis presents a potential therapeutic strategy for NSCLC.
Keywords:
CUL4BH2AK119 monoubiquitinationdouble-negative feedback looplung cancermicroRNA

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