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TET1 inhibits cell proliferation by inducing RASSF5 expression

Bo-Tai Li1, Chao Yu1, Ying Xu2

  • 1Life Sciences Institute, Zhejiang University, Hangzhou 301158, China.

Oncotarget
|November 22, 2017
PubMed

Insights

Tet methylcytosine dioxygenase 1 (TET1) suppresses ovarian cancer growth by increasing 5-hydroxymethylcytosine (5hmC) levels and upregulating the tumor suppressor Ras association domain family member 5 (RASSF5). TET1 acts as a key player in regulating ovarian cancer progression.

Area of Science:

  • Epigenetics
  • Cancer Biology
  • Molecular Oncology

Background:

  • Tet methylcytosine dioxygenases (TETs) oxidize 5-methylcytosine to 5-hydroxymethylcytosine (5hmC).
  • The specific role of TET1 in ovarian cancer cell proliferation and growth remains largely unexplored.

Purpose of the Study:

  • To investigate the function of TET1 in ovarian cancer.
  • To identify downstream targets and mechanisms through which TET1 influences ovarian cancer progression.

Main Methods:

  • Ovarian cancer cell lines were utilized for ectopic expression and depletion studies of TET1.
  • In vitro and in vivo functional assays assessed proliferation and colony formation.
  • RNA sequencing (RNA-seq) and quantitative reverse transcription PCR (qRT-PCR) identified downstream targets.
  • DNA methylation analysis of the RASSF5 promoter was performed.

Main Results:

  • Ectopic TET1 expression elevated 5hmC levels, inhibited ovarian cancer cell proliferation and colony formation.
  • TET1 overexpression suppressed tumor growth in vitro and in vivo, while TET1 depletion promoted it.
  • Ras association domain family member 5 (RASSF5) was identified as a key downstream target, with TET1 promoting its expression via demethylation of its promoter.
  • Inhibition of the CUL4-DDB1 ubiquitin ligase complex reduced 5hmC levels in ovarian cancer cells.

Conclusions:

  • TET1 functions as a tumor suppressor in ovarian cancer by increasing 5hmC and upregulating RASSF5 expression.
  • TET1-mediated RASSF5 upregulation inhibits ovarian cancer cell growth.
  • These findings elucidate a novel mechanism in ovarian cancer development and identify TET1 as a potential therapeutic target.
Keywords:
DNA methylationRASSF5TET1ovarian cancerproliferation

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