Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02215, USA.
Department of Informatics and Analytics, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
Nat Commun. 2022 Aug 25;13(1):4998. 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.
一些小细胞肺癌（SCLC）对组蛋白去甲基酶 LSD1 的抑制剂高度敏感。LSD1 抑制剂被认为通过阻断神经内分泌分化来发挥其抗增殖作用，但 LSD1 控制 SCLC 神经内分泌表型的机制尚不清楚。为了确定 LSD1 抑制剂在 SCLC 中的敏感性所需的基因，我们进行了正向选择全基因组 CRISPR/Cas9 功能丧失筛选，发现 ZFP36L1（一种稳定 mRNA 的 mRNA 结合蛋白）是 LSD1 抑制剂敏感性所必需的。LSD1 结合并抑制 ZFP36L1，而在 LSD1 抑制后，ZFP36L1 的表达得到恢复，这足以阻断 SCLC 神经内分泌分化表型并诱导非神经内分泌“炎症”表型。从机制上讲，ZFP36L1 结合并破坏 SOX2 和 INSM1 mRNA 的稳定性，这两种转录因子是 SCLC 神经内分泌分化所必需的。这项工作确定 ZFP36L1 为控制 SCLC 神经内分泌表型的 LSD1 靶基因，并证明调节谱系转录因子的 mRNA 稳定性控制神经内分泌到非神经内分泌的可塑性。
