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CSE1L is a negative regulator of the RB-DREAM pathway in p53 wild-type NSCLC and can be targeted using an HDAC1/2

Lei Duan1, Mehrdad Jafari Tadi1, Carl G Maki2

  • 1Department of Anatomy and Cell Biology, Rush University Medical Center, 600 S. Paulina Street, AcFac 507, Chicago, IL, 60612, USA.

Scientific Reports
|September 27, 2023
PubMed

Insights

CSE1L inhibits the RBL2-DREAM pathway in p53 wild-type non-small cell lung cancer (NSCLC). Targeting CSE1L with HDAC inhibitors like mocetinostat may improve therapy response in NSCLC patients.

Area of Science:

  • Cellular Biology
  • Molecular Oncology
  • Cancer Therapeutics

Background:

  • The p53 tumor suppressor pathway regulates cell cycle and apoptosis.
  • The RB-DREAM complex (including RBL2) is crucial for transcriptional repression.
  • RBL2-DREAM complex activity correlates with therapy response in p53 wild-type non-small cell lung cancer (NSCLC).

Purpose of the Study:

  • To identify novel regulators of the RBL2-DREAM pathway in NSCLC.
  • To investigate CSE1L as a potential therapeutic target in NSCLC.
  • To evaluate the efficacy of HDAC inhibitors in combination with targeting CSE1L.

Main Methods:

  • Investigated the role of CSE1L in regulating the RBL2-DREAM pathway in NSCLC cells.
  • Utilized CSE1L knockdown and treatment with mocetinostat (a HDAC1/2 inhibitor).
  • Assessed effects on p21 expression, RB1/RBL2 activation, DREAM target gene repression, and cellular toxicity in a p53-dependent manner.

Main Results:

  • CSE1L was identified as a novel inhibitor of the RBL2-DREAM pathway.
  • CSE1L knockdown or mocetinostat treatment reactivated RBL2-DREAM, increased p21, and repressed DREAM target genes.
  • These effects, including induced toxicity, were dependent on wild-type p53.
  • High CSE1L and DREAM target gene expression correlated with sensitivity to mocetinostat.

Conclusions:

  • CSE1L is a critical negative regulator of the RB-DREAM pathway in p53 wild-type NSCLC.
  • CSE1L can be indirectly targeted by HDAC1/2 inhibitors like mocetinostat.
  • CSE1L and DREAM target gene expression may serve as biomarkers for identifying NSCLC patients likely to respond to mocetinostat.

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