Regulation of neuroendocrine plasticity by the RNA-binding protein ZFP36L1

• DOI: 10.1038/s41467-022-31998-7
• Publication Date: 2022-08-25T12:03:16Z
• Authors: 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. Tolsto...; Charles M. Rudin; Triparna Sen; Sabina Signoretti; Matthew G. Oser
• Keywords: Neuroendocrine differentiation; Neuroendocrine cell

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