Regulation of neuroendocrine plasticity by the RNA-binding protein ZFP36L1.
Regulation of neuroendocrine plasticity by the RNA-binding protein ZFP36L1.
复制标题
DOI：
10.1038/s41467-022-31998-7
复制
发表时间：
2022-08-25
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
作者：
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诱导其抗增殖作用，但LSD1控制小细胞肺癌神经内分泌表型的机制尚不清楚。为了确定小细胞肺癌中LSD1抑制剂敏感性所需的基因，我们进行了全基因组CRISPR/Cas9功能丧失筛查，发现LSD1抑制剂敏感性需要ZFP36L1，一种破坏mRNAs稳定的mRNA结合蛋白。LSD1结合并抑制ZFP 36L1，当LSD1被抑制时，ZFP 36L1的表达恢复，这足以阻断小细胞肺癌的神经内分泌分化表型，并诱导非神经内分泌的“炎症”表型。在机制上，ZFP36L1结合和破坏SOX2和INSM1 mRNAs，这两个转录因子是小细胞肺癌神经内分泌分化所必需的。本研究确定ZFP36L1为LSD1靶基因，控制小细胞肺癌的神经内分泌表型，并证明调节家族转录因子的mRNA稳定性控制神经内分泌到非神经内分泌的可塑性。LSD1抑制抑制某些小细胞肺癌(SCLC)的神经内分泌表型。在这里，全基因组CRISPR/Cas9 LSD1抑制剂抗性筛查发现，mRNA结合蛋白ZFP36L1是一个由LSD1抑制的基因，当恢复时会抑制SCLC神经内分泌分化。
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.
登录
查看更多内容
影响因子：
8.8
作者：
Borromeo MD;Savage TK;Kollipara RK;He M;Augustyn A;Osborne JK;Girard L;Minna JD;Gazdar AF;Cobb MH;Johnson JE
通讯作者：
Johnson JE
影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
5.9
作者：
Cai L;Liu H;Huang F;Fujimoto J;Girard L;Chen J;Li Y;Zhang YA;Deb D;Stastny V;Pozo K;Kuo CS;Jia G;Yang C;Zou W;Alomar A;Huffman K;Papari-Zareei M;Yang L;Drapkin B;Akbay EA;Shames DS;Wistuba II;Wang T;Johnson JE;Xiao G;DeBerardinis RJ;Minna JD;Xie Y;Gazdar AF
通讯作者：
Gazdar AF
影响因子：
13.6
作者：
Koduri V;Duplaquet L;Lampson BL;Wang AC;Sabet AH;Ishoey M;Paulk J;Teng M;Harris IS;Endress JE;Liu X;Dasilva E;Paulo JA;Briggs KJ;Doench JG;Ott CJ;Zhang T;Donovan KA;Fischer ES;Gygi SP;Gray NS;Bradner J;Medin JA;Buhrlage SJ;Oser MG;Kaelin WG Jr
通讯作者：
Kaelin WG Jr
影响因子：
64.5
作者：
Klose, Robert J.;Yan, Qin;Kaelin, William G., Jr.
通讯作者：
Kaelin, William G., Jr.