HSF1 facilitates the multistep process of lymphatic metastasis in bladder cancer via a novel PRMT5-WDR5-dependent transcriptional program.
HSF1 facilitates the multistep process of lymphatic metastasis in bladder cancer via a novel PRMT5-WDR5-dependent transcriptional program.
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DOI：
10.1002/cac2.12284
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发表时间：
2022-05
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淋巴转移与膀胱癌患者的预后不良相关，治疗选择有限。新的证据表明，热休克因子1（HSF 1）驱动多样化的转录组，以促进肿瘤生长，并作为一个有前途的治疗靶点。然而，HSF 1在淋巴转移中的作用仍然很大程度上未知。本研究旨在阐明HSF 1在膀胱癌淋巴结转移中的临床作用及机制，并探讨其治疗潜力。我们从高表达的热休克因子（HSFs）和热休克蛋白（HSPs）中筛选出与淋巴结转移最相关的基因，并在三个队列中分析其临床相关性。在HSF 1沉默和恢复模型中进行了体外和体内功能试验。我们还使用免疫共沉淀法鉴定HSF 1的结合蛋白，染色质免疫沉淀法和双荧光素酶报告基因测定法研究HSF 1指导的转录程序。在膀胱癌的腘淋巴结转移模型和患者来源的异种移植模型中评价了HSF 1的药理学抑制剂KRIBB 11。HSF 1表达与膀胱癌淋巴结转移、肿瘤分期、恶性程度及预后不良呈正相关。重要的是，HSF 1增强原发性肿瘤中癌细胞的上皮间质转化（EMT）以启动转移、淋巴结中癌细胞的增殖和巨噬细胞浸润以促进多步淋巴转移。HSF 1与蛋白质精氨酸甲基转移酶5（PRMT 5）相互作用，共同诱导组蛋白H3在精氨酸2处的单甲基化（H3 R2 me 1）和组蛋白H3在精氨酸2处的对称二甲基化（H3 R2 me 2s）。这招募了WD重复结构域5（WDR 5）/混合谱系白血病（MLL）复合物，以增加组蛋白H3在赖氨酸4（H3 K4 me 3）的三甲基化;导致淋巴增强子结合因子1（LEF 1），基质金属肽酶9（MMP 9），C-C基序趋化因子配体20（CCL 20）和E2 F转录因子2（E2 F2）的上调。应用KRIBB 11显著抑制膀胱癌的淋巴结转移，且无显著毒性。我们的研究结果揭示了在膀胱癌淋巴转移的多步骤过程中由HSF 1-PRMT 5-WDR 5轴指导的新的转录程序。以HSF 1为靶点治疗膀胱癌淋巴结转移可能是一种多效且有前景的治疗策略。
Lymphatic metastasis has been associated with poor prognosis in bladder cancer patients with limited therapeutic options. Emerging evidence shows that heat shock factor 1 (HSF1) drives diversified transcriptome to promote tumor growth and serves as a promising therapeutic target. However, the roles of HSF1 in lymphatic metastasis remain largely unknown. Herein, we aimed to illustrate the clinical roles and mechanisms of HSF1 in the lymphatic metastasis of bladder cancer and explore its therapeutic potential. We screened the most relevant gene to lymphatic metastasis among overexpressed heat shock factors (HSFs) and heat shock proteins (HSPs), and analyzed its clinical relevance in three cohorts. Functional in vitro and in vivo assays were performed in HSF1‐silenced and ‐regained models. We also used Co‐immunoprecipitation to identify the binding proteins of HSF1 and chromatin immunoprecipitation and dual‐luciferase reporter assays to investigate the transcriptional program directed by HSF1. The pharmacological inhibitor of HSF1, KRIBB11, was evaluated in popliteal lymph node metastasis models and patient‐derived xenograft models of bladder cancer. HSF1 expression was positively associated with lymphatic metastasis status, tumor stage, advanced grade, and poor prognosis of bladder cancer. Importantly, HSF1 enhanced the epithelial‐mesenchymal transition (EMT) of cancer cells in primary tumor to initiate metastasis, proliferation of cancer cells in lymph nodes, and macrophages infiltration to facilitate multistep lymphatic metastasis. Mechanistically, HSF1 interacted with protein arginine methyltransferase 5 (PRMT5) and jointly induced the monomethylation of histone H3 at arginine 2 (H3R2me1) and symmetric dimethylation of histone H3 at arginine 2 (H3R2me2s). This recruited the WD repeat domain 5 (WDR5)/mixed‐lineage leukemia (MLL) complex to increase the trimethylation of histone H3 at lysine 4 (H3K4me3); resulting in upregulation of lymphoid enhancer‐binding factor 1 (LEF1), matrix metallopeptidase 9 (MMP9), C‐C motif chemokine ligand 20 (CCL20), and E2F transcription factor 2 (E2F2). Application of KRIBB11 significantly inhibited the lymphatic metastasis of bladder cancer with no significant toxicity. Our findings reveal a novel transcriptional program directed by the HSF1‐PRMT5‐WDR5 axis during the multistep process of lymphatic metastasis in bladder cancer. Targeting HSF1 could be a multipotent and promising therapeutic strategy for bladder cancer patients with lymphatic metastasis.