PDF(Pubmed)
Abstract：
Stress-induced promoter-associated and antisense lncRNAs (si-paancRNAs) originate from a reservoir of oxidative stress (OS)-specific promoters via RNAPII pausing-mediated divergent antisense transcription. Several studies have shown that the KDM7A divergent transcript gene (KDM7A-DT), which encodes a si-paancRNA, is overexpressed in some cancer types. However, the mechanisms of this overexpression and its corresponding roles in oncogenesis and cancer progression are poorly understood. We found that KDM7A-DT expression is correlated with highly aggressive cancer types and specific inherently determined subtypes (such as ductal invasive breast carcinoma (BRCA) basal subtype). Its regulation is determined by missense TP53 mutations in a subtype-specific context. KDM7A-DT transcribes several intermediate-sized ncRNAs and a full-length transcript, exhibiting distinct expression and localization patterns. Overexpression of KDM7A-DT upregulates TP53 protein expression and H2AX phosphorylation in nonmalignant fibroblasts, while in semi-transformed fibroblasts, OS superinduces KDM7A-DT expression in a TP53-dependent manner. KDM7A-DT knockdown and gene expression profiling in TP53-missense mutated luminal A BRCA variant, where it is abundantly expressed, indicate its significant role in cancer pathways. Endogenous over-expression of KDM7A-DT inhibits DNA damage response/repair (DDR/R) via the TP53BP1-mediated pathway, reducing apoptosis and promoting G2/M checkpoint arrest. Higher KDM7A-DT expression in BRCA is associated with KDM7A-DT locus gain/amplification, higher histologic grade, aneuploidy, hypoxia, immune modulation scores, and activation of the c-myc pathway. Higher KDM7A-DT expression is associated with relatively poor survival outcomes in patients with luminal A or Basal subtypes. In contrast, it is associated with favorable outcomes in patients with HER2+ER- or luminal B subtypes. KDM7A-DT levels are coregulated with critical transcripts and proteins aberrantly expressed in BRCA, including those involved in DNA repair via non-homologous end joining and epithelial-to-mesenchymal transition pathway. In summary, KDM7A-DT and its si-lncRNA exhibit several intrinsic biological and clinical characteristics that suggest important roles in invasive BRCA and its subtypes. KDM7A-DT-defined mRNA and protein subnetworks offer resources for identifying clinically relevant RNA-based signatures and prospective targets for therapeutic intervention.
摘要：
应激诱导的启动子相关和反义lncRNAs（si-paancRNAs）起源于通过RNAPII暂停介导的发散反义转录的氧化应激（OS）特异性启动子库。一些研究表明，KDM7A分歧转录基因（KDM7A-DT），编码si-paancRNA,在某些癌症类型中过表达。然而,这种过度表达的机制及其在肿瘤发生和癌症进展中的相应作用知之甚少。我们发现KDM7A-DT表达与高度侵袭性癌症类型和特定的固有确定亚型（例如导管浸润性乳腺癌（BRCA）基底亚型）相关。其调节由亚型特异性环境中的错义TP53突变决定。KDM7A-DT转录几个中等大小的ncRNAs和全长转录本，表现出不同的表达和定位模式。KDM7A-DT的过表达上调非恶性成纤维细胞中TP53蛋白表达和H2AX磷酸化,而在半转化的成纤维细胞中，OS以TP53依赖性方式超诱导KDM7A-DT表达。TP53错义突变的腔内ABRCA变体中的KDM7A-DT敲低和基因表达谱，它被大量表达，表明其在癌症途径中的重要作用。KDM7A-DT的内源性过表达通过TP53BP1介导的途径抑制DNA损伤反应/修复（DDR/R），减少细胞凋亡并促进G2/M检查点的停止。BRCA中更高的KDM7A-DT表达与KDM7A-DT基因座增益/扩增相关，组织学分级较高，非整倍体,缺氧,免疫调节评分，和c-myc途径的激活。较高的KDM7A-DT表达与腔A或基底亚型患者相对较差的生存结果相关。相比之下,它与HER2+ER-或管腔B亚型患者的良好结局相关.KDM7A-DT水平与BRCA中异常表达的关键转录本和蛋白质共同调节，包括通过非同源末端连接和上皮-间质转化途径参与DNA修复的那些。总之,KDM7A-DT及其si-lncRNA表现出一些内在的生物学和临床特征，表明在侵袭性BRCA及其亚型中具有重要作用。KDM7A-DT定义的mRNA和蛋白质子网络为识别临床相关的基于RNA的特征和治疗干预的前瞻性靶标提供了资源。
