A Novel Therapeutic Strategy Targeting the Mesenchymal Phenotype of Malignant Pleural Mesothelioma by Suppressing LSD1
A Novel Therapeutic Strategy Targeting the Mesenchymal Phenotype of Malignant Pleural Mesothelioma by Suppressing LSD1
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通过抑制 LSD1 靶向恶性胸膜间皮瘤间质表型的新治疗策略
DOI：
10.1158/1541-7786.mcr-21-0230
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发表时间：
2021
影响因子：
5.2
通讯作者：
Takahashi K
中科院分区：
文献类型：
--
作者：
Wirawan Aditya;Tajima Ken;Takahashi Fumiyuki;Mitsuishi Yoichiro;Winardi Wira;Hidayat Moulid;Hayakawa Daisuke;Matsumoto Naohisa;Izumi Kenta;Asao Tetsuhiko;Ko Ryo;Shimada Naoko;Takamochi Kazuya;Suzuki Kenji;Abe Masaaki;Hino Okio;Sekido Yoshitaka;Takahashi K
恶性胸膜间皮瘤（MPM）是一种高度侵袭性的肿瘤，具有较低的总生存率;然而，在过去的15年中，没有显着的治疗进展。大规模的分子研究已经确定了一个预后不良的MPM子集与上皮间质转化（EMT），可能有助于对化疗的耐药性，这表明EMT可以有针对性地治疗MPM患者。以前，我们报道了组蛋白修饰剂调节EMT可能是治疗靶点;因此，在这项研究中，我们研究了靶向赖氨酸特异性脱甲基酶1（LSD 1/KDM 1），一种负责脱甲基化组蛋白H3赖氨酸4和赖氨酸9的组蛋白修饰酶，是否可以代表MPM的一种新的治疗策略。我们抑制LSD 1并使用EMT标记表达和伤口愈合测定研究EMT表型;使用凋亡测定研究化学敏感性。我们发现，抑制LSD 1诱导肉瘤样MPM细胞的上皮表型，而减弱间充质表型敏感的MPM细胞顺铂诱导的凋亡。随后的全基因组鉴定、全面的微阵列分析和使用测序的转座酶可降解染色质测定（ATAC-seq）评估染色质可及性的全基因组变化表明，LSD 1直接调节乳脂球蛋白E8（MFGE 8），这是一种参与FAK途径的整合素配体。此外，我们还发现LSD 1通过激活FAK-AKT-GSK 3 β通路，通过MFGE 8和Snail表达的正反馈环调控间充质细胞表型和细胞凋亡，从而导致顺铂耐药。
Malignant pleural mesothelioma (MPM) is a highly aggressive tumor that has a low overall survival; however, no significant treatment advances have been made in the past 15 years. Large-scale molecular studies have identified a poor prognostic subset of MPM linked to the epithelial–mesenchymal transition (EMT) that may contribute toward resistance to chemotherapy, suggesting that EMT could be targeted to treat patients with MPM. Previously, we reported that histone modifiers regulating EMT could be therapeutic targets; therefore, in this study, we investigated whether targeting lysine-specific demethylase 1 (LSD1/KDM1), a histone-modifying enzyme responsible for demethylating histone H3 lysine 4 and lysine 9, could represent a novel therapeutic strategy for MPM. We suppressed LSD1 and investigated the EMT phenotype using EMT marker expression and wound-healing assay; and chemosensitivity using apoptosis assay. We found that suppressing LSD1 induces an epithelial phenotype in sarcomatoid MPM cells, while attenuating the mesenchymal phenotype sensitized MPM cells to cisplatin-induced apoptosis. Subsequent genome-wide identification, comprehensive microarray analysis, and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) to assess genome-wide changes in chromatin accessibility suggested that LSD1 directly regulates milk fat globulin protein E8 (MFGE8), an integrin ligand that is involved in the FAK pathway. Furthermore, we found that LSD1 regulates the mesenchymal phenotype and apoptosis by activating the FAK–AKT–GSK3β pathway via a positive feedback loop involving MFGE8 and Snail expression, thereby leading to cisplatin resistance.ImplicationsThis study suggests that LSD1 regulates the mesenchymal phenotype and apoptosis, and that LSD1 inhibitors could be combined with the cisplatin as a novel therapy for patients with MPM.
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影响因子：
11.2
作者：
Jinushi, Masahisa;Nakazaki, Yukoh;Dranoff, Glenn
通讯作者：
Dranoff, Glenn
影响因子：
11.2
作者：
Yang C;Hayashida T;Forster N;Li C;Shen D;Maheswaran S;Chen L;Anderson KS;Ellisen LW;Sgroi D;Schmidt EV
通讯作者：
Schmidt EV
四种恶性胸膜的建立和表征！
DOI：
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发表时间：
2006
期刊：
影响因子：
--
作者：
Usami N;Fukui T;Kondo M;Taniguchi T;Yokoi K;Shimokata K;Hida T;Sekido Y
通讯作者：
Sekido Y
Hirano,H.：“水稻 wx 基因座的分子特征。”
DOI：
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发表时间：
--
期刊：
影响因子：
--
作者：
通讯作者：
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影响因子：
8.8
作者：
Luo, Huacheng;Shenoy, Anitha K.;Lu, Jianrong
通讯作者：
Lu, Jianrong