Regulation of neuroendocrine plasticity by the RNA-binding protein ZFP36L1

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. Barbie, Michael Y. Tolstorukov, Charles M. Rudin, Triparna Sen, Sabina Signoretti and Matthew G. Oser ()
Additional contact information
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
Julie-Aurore Losman: Harvard Medical School
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

Nature Communications, 2022, vol. 13, issue 1, 1-22

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-31998-7

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