Regulation of neuroendocrine plasticity by the RNA-binding protein ZFP36L1

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.

Mammalian SWI/SNF complex activity regulates POU2F3 and constitutes a targetable dependency in small cell lung cancer

“…Finally, recent evidence is emerging that SCLC subtypes could be regulated by distinct epigenetic modifiers. Our data suggest that only the POU2F3 subtype is highly dependent on mSWI/SNF; in parallel, previous studies found that some SCLC cell lines of the ASCL1 subtype are highly dependent on the histone demethylase LSD1, where LSD1 is dispensable in other SCLC subtypes including in POU2F3-positive SCLC 49,50 . As such, the identification of the biochemical and chromatin regulatory interplay between lineage-specific TFs and each distinct chromatin regulatory entity is likely to yield improved understanding regarding SCLC pathogenesis and uncover additional therapeutic vulnerabilities associated with each SCLC subtype.…”

LSD1 inhibition suppresses ASCL1 and de-represses YAP1 to drive potent activity against neuroendocrine prostate cancer

“…We then focused on previously published NE-associated gene signatures. We observed a significant downregulation of NE-associated gene signatures based on the Chen (28) ( Figure 4E, S6B ) and Beltran (8) datasets ( Figure 4F, S6C). This trend was consistently mirrored in other NE-associated gene signatures ( Figure 4F ), leading us to investigate canonical neuronal transcription factors as a mechanism for the downregulation of the NE transcriptional program.…”

EIF6 conditions drug-tolerant persister-like transdifferentiation in small cell lung carcinoma

“…3c). Conversely, eIF6 knockdown markedly increased the neuroendocrine gene signature 42,43 (Fig. 3b and Supplementary Table 3), encompassing HES6, TOP2A, DLL3, NEUROD1, ASCL1, INSM1 and CHGA (Fig.…”

“…Gene set enrichment analysis of cytoplasmic RNA-seq was implemented by using GSEA software version 4.1.0. GSEA was performed using Hallmark EMT, 'Top 100 neuroendocrine genes' (Supplementary Table 3) 43 and KEGG in Fig. 3a,b,k respectively.…”