组蛋白变体H2AZ1在非小细胞肺癌中的作用及分子机制研究

肺癌是导致癌症相关死亡最多的癌种。多数肺癌患者在早期经治疗总体预后较好，一旦发生进展及转移，则预后极差。由于肺癌进展的详细机制并不完全清楚，对于中晚期肺癌患者，目前几乎没有针对性药物或者手段能够挽救。因此，研究肺癌进展的具体机制对探索新的治疗方式、改善患者预后是至关重要的。

本研究分析了一系列的肺癌肿瘤样本基因芯片表达数据和TCGA肺癌RNA-seq数据, 发现H2AZ1 mRNA在临床肺癌组织中高表达（相对癌旁正常组织）。H2AZ1在低分化肺腺癌和淋巴结转移阳性的肿瘤组织中高表达且与病人预后差相关。然而，H2AZ1在肺癌中的具体作用机制并不清楚。因此，我们从体外功能实验、细胞周期、凋亡、自噬、肺癌关键信号通路调控、H2AZ1在不同肺癌细胞系染色质的分布特点和规律、H2AZ1在不同肺癌细胞系中对染色质可及性的影响等方面进行研究，利用RNA-seq、CUT&Tag、ATAC-seq等实验技术全面揭示 H2AZ1在肺癌的作用机制。

用siRNA敲降 H2AZ1后，细胞增殖、克隆形成、迁移和侵袭能力下降，细胞周期阻滞。在分子机制方面，我们发现H2AZ1调控肺癌中多个关键癌症相关信号通路，H2AZ1通过HIF1A调控EGFR、AXL的表达。H2AZ1对HIF1A-EGFR/AXL轴的调控可能是通过RELA介导的。敲降MYC、MET或RELA可减少H2AZ1的表达。同时，研究发现，在肺癌细胞中，H2AZ1的敲降可以诱导肺癌细胞发生自噬，H2AZ1敲降对自噬的诱导可能是通过p-CAMKK2-p-AMPK-p-mTOR信号通路。最后，我们对RNA-seq、CUT&Tag、ATAC-seq的组学数据进行了分析。CUT&Tag显示H2AZ1与转录起始位点结合并影响多种癌症相关的信号通路，ATAC-seq显示H2AZ1在不同细胞系间对染色质可及性的影响更具有异质性。我们对RNA-seq、CUT&Tag、ATAC-seq的组学数据进行了整合分析发现H2AZ1在基因转录起始位点有三种染色质位置模型，对H2AZ1在肺癌染色质中分布规律有了进一步的认识。

综上所述，该课题从不同层面解析了H2AZ1在肺癌中的功能机制，通过研究得出以下结论：（1）H2AZ1在肺癌中高表达，并与患者的不良生存率相关。（2）H2AZ1沉默影响细胞增殖和侵袭，诱导细胞周期阻滞，并通过p-CAMKK2-p-AMPK-p-mTOR信号通路诱导肺癌细胞自噬。（3）H2AZ1调控多个癌基因表达，并与多个关键的癌症相关信号通路相关。（4）H2AZ1受MYC/MET/RELA调节，并通过对HIF1A-EGFR/AXL信号通路的调控促进肺癌进展。（5）H2AZ1在非小细胞肺癌细胞染色体中的定位及分布有三种模型，影响多个癌症相关通路。对H2AZ1或其下游蛋白进行干预具有临床治疗转化潜力。

Lung cancer is the leading cause of cancer-related deaths globally. When diagnosed and treated in the early stages, patients with lung cancer have a relatively good prognosis. Unfortunately, once the cancer has progressed, the prognosis becomes extremely poor. Despite significant advancements in cancer research, the detailed mechanisms of lung cancer progression are still not fully understood, which limits the availability of specific drugs or tools to save patients with advanced lung cancer. Hence, there is a critical need to explore the specific mechanisms of lung cancer progression to develop more effective treatments and improve patient outcomes.

In this study, we analyzed gene chip expression data of lung cancer tumor samples and RNA-seq data from TCGA, and found that H2AZ1 mRNA was highly expressed in clinical lung cancer tissue compared to adjacent normal tissue. Furthermore, we observed high H2AZ1 expression in poorly differentiated lung adenocarcinoma and tumor tissue with positive lymph node metastasis, which was associated with poor patient prognosis. Despite this, the specific mechanism of H2AZ1 in lung cancer remains unclear. Therefore, we conducted research on H2AZ1's mechanism in lung cancer, including in vitro functional experiments, cell cycle, apoptosis, autophagy, regulation of key signaling pathways in lung cancer, distribution patterns and regularities of H2AZ1 in chromatin of different lung cancer cell lines, and the impact of H2AZ1 on chromatin accessibility in different lung cancer cell lines. We used experimental techniques such as RNA-seq, CUT&Tag, and ATAC-seq to comprehensively reveal H2AZ1's role in lung cancer.

After knocking down H2AZ1 with siRNA, cell proliferation, clone formation, migration and invasion ability decreased, and cell cycle was arrested. In terms of molecular mechanisms, we found that H2AZ1 regulates several key cancer-related signaling pathways in lung cancer. H2AZ1 regulates the expression of EGFR, and AXL via HIF1A. The regulation of HIF1A-EGFR/AXL axis by H2AZ1 may be mediated through RELA. Further, we found that knockdown of MYC, MET or RELA could reduce the H2AZ1 expression. Meanwhile, knockdown of H2AZ1 could induce autophagy in lung cancer cells, which may be through the p-CAMKK2-p-AMPK-p-mTOR signaling pathway. Finally, we analyzed the data of RNA-seq, CUT&Tag, and ATAC-seq. The results of CUT&Tag showed that H2AZ1 binds to Transcription Start Site and affects multiple cancer-related signaling pathways, and the results of ATAC-seq showed that the effect of H2AZ1 on chromatin accessibility was more heterogeneous among different cell lines. We have consolidated and analyzed the data from RNA-seq, CUT&Tag, and ATAC-seq and identified three models of H2AZ1 chromatin location around TSS in lung cancer cells, which provided further insight into the distribution pattern of H2AZ1 in lung cancer chromatin.

In summary, the functions and mechanisms of H2AZ1 in lung cancer were analyzed at different levels and the following conclusions were drawn from the study: (1) H2AZ1 is highly expressed in lung cancer and correlates with poor patient survival. (2) Silencing H2AZ1 impairs cell proliferation and invasion, induces cell cycle arrest, and triggers autophagy via the p-CAMKK2-p-AMPK-p-mTOR signaling pathway. (3) H2AZ1 regulates multiple oncogenes expression and several key cancer-related signaling pathways including HIF1A-EGFR/AXL signaling. (4) H2AZ1 may be regulated by MYC, MET, or RELA separately. (5) Three H2AZ1 chromatin deposition models exist around the Transcription Start Site, which impacts multiple cancer-related pathways. Intervention in H2AZ1 or its downstream signaling may have potential clinical translational therapy.

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