Rationale: Paclitaxel resistance is a major concern when treating triple-negative breast cancer (TNBC) patients. We aimed to identify candidates causing paclitaxel resistance and explore their significance in TNBC therapeutics./nMethods: A genome-wide CRISPR screening, integrated with transcriptome analyses, was performed to identify candidates involved in paclitaxel-resistant TNBCs. Cell proliferation, cytotoxicity, immunofluorescent staining, and xenograft assays were conducted to verify the phenotypes of paclitaxel resistance induced by candidate genes, both in vitro and in vivo. RNA sequencing, Western blotting, and chromatin immunoprecipitation assays were used to explore the underlying mechanisms./nResults: MEF2-interacting transcriptional repressor (MITR), the truncated isoform of histone deacetylase 9 (HDAC9) lacking the deacetylation domain, was enriched in paclitaxel-resistant cells. Elevated MITR expression resulted in increased interleukin-11 (IL11) expression and activation of downstream JAK/STAT3 signaling. Mechanistically, MITR counteracted MEF2A-induced transcriptional suppression of IL11, ultimately causing paclitaxel resistance. By contrast, pharmacological inhibition of JAK1/2 by ruxolitinib reversed paclitaxel resistance both in vitro and in vivo./nConclusion: Our in vitro and in vivo genetic and cellular analyses elucidated the pivotal role of MITR/MEF2A/IL11 axis in paclitaxel resistance and provided a novel therapeutic strategy for TNBC patients to overcome poor chemotherapy responses.

中文翻译：

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整合全基因组筛选鉴定出截短的 HDAC9 作为三阴性乳腺癌紫杉醇耐药的关键调节剂

基本原理：治疗三阴性乳腺癌 (TNBC) 患者时，紫杉醇耐药性是一个主要问题。我们旨在确定导致紫杉醇耐药的候选药物并探索它们在 TNBC 治疗中的重要性。/n方法：进行全基因组 CRISPR 筛选，结合转录组分析，以确定参与紫杉醇耐药 TNBC 的候选药物。进行细胞增殖、细胞毒性、免疫荧光染色和异种移植试验，以验证候选基因在体外和体内诱导的紫杉醇抗性表型。RNA 测序、蛋白质印迹和染色质免疫沉淀分析用于探索潜在机制。/n 结果：MEF2 相互作用转录抑制因子 (MITR)，即缺乏脱乙酰域的组蛋白脱乙酰酶 9 (HDAC9) 的截短同种型，富含紫杉醇抗性细胞。升高的 MITR 表达导致增加的白细胞介素 11 (IL11) 表达和下游 JAK/STAT3 信号传导的激活。从机制上讲，MITR 抵消了 MEF2A 诱导的 IL11 转录抑制，最终导致紫杉醇耐药。相比之下，鲁索替尼对 JAK1/2 的药理学抑制在体外和体内逆转了紫杉醇耐药性。/n结论：我们的体外和体内 遗传和细胞分析阐明了 MITR/MEF2A/IL11 轴在紫杉醇抵抗中的关键作用，并为 TNBC 患者克服化疗反应不佳提供了一种新的治疗策略。