Regulation of neuroendocrine plasticity by the RNA-binding protein ZFP36L1

• Published in: Nature communications Vol. 13; no. 1; pp. 4998 - 22
• Main Authors: Chen, Hsiao-Yun, Durmaz, Yavuz T., Li, Yixiang, Sabet, Amin H., Vajdi, Amir, Denize, Thomas, Walton, Emily, Laimon, Yasmin Nabil, Doench, John G., Mahadevan, Navin R., Losman, Julie-Aurore, Barbie, David A., Tolstorukov, Michael Y., Rudin, Charles M., Sen, Triparna, Signoretti, Sabina, Oser, Matthew G.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 25.08.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 49/47; 49/91; 631/208/199; 631/208/200; 631/67/1612/2143; Blocking; Butyrate Response Factor 1 - metabolism; Cancer; CRISPR; Differentiation; Genomes; Genotype & phenotype; Histone Demethylases - genetics; Histone Demethylases - metabolism; Histones; Humanities and Social Sciences; Humans; Inflammation; Inhibitors; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Lungs; mRNA stability; multidisciplinary; Neuroendocrine system; Phenotypes; Plastic properties; Plasticity; Positive selection; Proteins; Repressor Proteins - metabolism; RNA-binding protein; RNA-Binding Proteins - genetics; Science; Science (multidisciplinary); Sensitivity; Small Cell Lung Carcinoma - metabolism; Small Cell Lung Carcinoma - pathology; Transcription factors; Transcription Factors - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-31998-7

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. LSD1 inhibition blocks the neuroendocrine phenotype of some small cell lung cancers (SCLCs). Here, a genome-wide CRISPR/Cas9 LSD1 inhibitor resistance screen identifies the mRNA-binding protein ZFP36L1 as a gene repressed by LSD1 that when restored inhibits SCLC neuroendocrine differentiation.