Related Experiment Video

Updated: Aug 31, 2025

Identification of Transcription Factor Regulators using Medium-Throughput Screening of Arrayed Libraries and a Dual-Luciferase-Based Reporter
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Identification of Transcription Factor Regulators using Medium-Throughput Screening of Arrayed Libraries and a Dual-Luciferase-Based Reporter

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Regulation of neuroendocrine plasticity by the RNA-binding protein ZFP36L1

Hsiao-Yun Chen1, Yavuz T Durmaz1, Yixiang Li1

  • 1Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02215, USA.

Nature Communications
|August 25, 2022
PubMed

Insights

Small cell lung cancer (SCLC) cells sensitive to LSD1 inhibitors rely on ZFP36L1. Restoring ZFP36L1 blocks neuroendocrine differentiation, revealing a new therapeutic target for SCLC treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Small cell lung cancer (SCLC) exhibits sensitivity to LSD1 inhibitors.
  • LSD1 inhibitors' anti-proliferative effects are linked to blocking neuroendocrine differentiation.
  • The precise mechanisms of LSD1 in controlling the SCLC neuroendocrine phenotype remain unclear.

Purpose of the Study:

  • To identify genes crucial for LSD1 inhibitor sensitivity in SCLC.
  • To elucidate the role of ZFP36L1 in LSD1 inhibitor response and SCLC neuroendocrine plasticity.

Main Methods:

  • Genome-wide CRISPR/Cas9 loss-of-function screen for positive selection.
  • Analysis of ZFP36L1's interaction with LSD1 and its target mRNAs (SOX2, INSM1).
  • Assessment of ZFP36L1's impact on SCLC neuroendocrine differentiation and phenotype.

Main Results:

  • ZFP36L1 was identified as essential for LSD1 inhibitor sensitivity in SCLC.
  • LSD1 represses ZFP36L1; LSD1 inhibition restores ZFP36L1 expression.
  • Restored ZFP36L1 blocks SCLC neuroendocrine differentiation, inducing an "inflammatory" phenotype.

Conclusions:

  • ZFP36L1 is an LSD1 target gene that regulates the SCLC neuroendocrine phenotype.
  • Modulating mRNA stability of lineage transcription factors controls neuroendocrine plasticity in SCLC.
  • ZFP36L1 represents a potential therapeutic target for SCLC treatment.

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