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Regulation of neuroendocrine plasticity by the RNA-binding protein ZFP36L1

Author

Listed:
  • Hsiao-Yun Chen

    (Harvard Medical School)

  • Yavuz T. Durmaz

    (Harvard Medical School)

  • Yixiang Li

    (Harvard Medical School)

  • Amin H. Sabet

    (Harvard Medical School)

  • Amir Vajdi

    (Dana-Farber Cancer Institute)

  • Thomas Denize

    (Harvard Medical School)

  • Emily Walton

    (Harvard Medical School)

  • Yasmin Nabil Laimon

    (Harvard Medical School)

  • John G. Doench

    (Broad Institute of MIT and Harvard)

  • Navin R. Mahadevan

    (Harvard Medical School
    Harvard Medical School)

  • Julie-Aurore Losman

    (Harvard Medical School
    Brigham and Women’s Hospital)

  • David A. Barbie

    (Harvard Medical School)

  • Michael Y. Tolstorukov

    (Dana-Farber Cancer Institute)

  • Charles M. Rudin

    (Memorial Sloan Kettering Cancer Center)

  • Triparna Sen

    (Icahn School of Medicine at Mount Sinai)

  • Sabina Signoretti

    (Harvard Medical School)

  • Matthew G. Oser

    (Harvard Medical School
    Harvard Medical School)

Abstract

Some small cell lung cancers (SCLCs) are highly sensitive to inhibitors of the histone demethylase LSD1. LSD1 inhibitors are thought to induce their anti-proliferative effects by blocking neuroendocrine differentiation, but the mechanisms by which LSD1 controls the SCLC neuroendocrine phenotype are not well understood. To identify genes required for LSD1 inhibitor sensitivity in SCLC, we performed a positive selection genome-wide CRISPR/Cas9 loss of function screen and found that ZFP36L1, an mRNA-binding protein that destabilizes mRNAs, is required for LSD1 inhibitor sensitivity. LSD1 binds and represses ZFP36L1 and upon LSD1 inhibition, ZFP36L1 expression is restored, which is sufficient to block the SCLC neuroendocrine differentiation phenotype and induce a non-neuroendocrine “inflammatory” phenotype. Mechanistically, ZFP36L1 binds and destabilizes SOX2 and INSM1 mRNAs, two transcription factors that are required for SCLC neuroendocrine differentiation. This work identifies ZFP36L1 as an LSD1 target gene that controls the SCLC neuroendocrine phenotype and demonstrates that modulating mRNA stability of lineage transcription factors controls neuroendocrine to non-neuroendocrine plasticity.

Suggested Citation

  • Hsiao-Yun Chen & Yavuz T. Durmaz & Yixiang Li & Amin H. Sabet & Amir Vajdi & Thomas Denize & Emily Walton & Yasmin Nabil Laimon & John G. Doench & Navin R. Mahadevan & Julie-Aurore Losman & David A. B, 2022. "Regulation of neuroendocrine plasticity by the RNA-binding protein ZFP36L1," Nature Communications, Nature, vol. 13(1), pages 1-22, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31998-7
    DOI: 10.1038/s41467-022-31998-7
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