AbstractThe transcription factor regulatory factor X 7 (RFX7) has been identified as a tumor suppressor that is recurrently mutated in lymphoid cancers and appears to be dysregulated in many other cancers. RFX7 is activated by the well-known tumor suppressor p53 and regulates several other known tumor suppressor genes.

摘要转录因子调节因子X 7（RFX7）已被鉴定为一种肿瘤抑制因子，在淋巴癌中反复突变，在许多其他癌症中似乎失调。RFX7被众所周知的肿瘤抑制基因p53激活，并调节其他几种已知的肿瘤抑制基因。

However, what other factors regulate RFX7 and its target genes remains unclear. Here, reporter gene assays were used to identify that RFX7 regulates the tumor suppressor gene PDCD4 through direct interaction with its X-box promoter motif. We utilized mass spectrometry to identify factors that bind to DNA together with RFX7.

然而，还有哪些其他因素调节RFX7及其靶基因仍不清楚。在这里，使用报告基因测定来鉴定RFX7通过与其X-box启动子基序的直接相互作用来调节肿瘤抑制基因PDCD4。我们利用质谱法鉴定了与RFX7结合DNA的因子。

In addition to RFX7, we also identified RFX5, RFXAP, RFXANK, and ANKRA2 that bind to the X-box motif in the PDCD4 promoter. We demonstrate that ANKRA2 is a bona fide direct p53 target gene. We used transcriptome analyses in two cell systems to identify genes regulated by ANKRA2, its sibling RFXANK, and RFX7.

除RFX7外，我们还鉴定了RFX5，RFXAP，RFXANK和ANKRA2，它们与PDCD4启动子中的X-box基序结合。我们证明ANKRA2是真正的直接p53靶基因。我们在两个细胞系统中使用转录组分析来鉴定由ANKRA2，其同胞RFXANK和RFX7调控的基因。

These results revealed that ANKRA2 functions as a critical cofactor of RFX7, whereas RFXANK regulates largely distinct gene sets..

这些结果表明，ANKRA2是RFX7的关键辅因子，而RFXANK调节着很大程度上不同的基因组。。

IntroductionRFX7 has recently emerged as a tumor suppressor that is recurrently mutated in hematopoietic cancers [1]. For example, RFX7 mutations have been implied to be cancer drivers in Burkitt lymphoma [2, 3] and chronic lymphocytic leukemia [4]. In strong support of its tumor suppressor function, loss of RFX7 accelerated B cell lymphomagenesis in mouse models [5].

引言RFX7最近成为一种在造血系统癌症中反复突变的肿瘤抑制因子。例如，RFX7突变被认为是伯基特淋巴瘤（2，3）和慢性淋巴细胞白血病（4）的癌症驱动因素。在强烈支持其肿瘤抑制功能的同时，RFX7的缺失加速了小鼠模型中B细胞淋巴瘤的发生（5）。

In addition, RFX7 appears to be deactivated in many cancers in which it is not mutated [6], making RFX7 reactivation an intriguing target for cancer therapy. Besides cancer, RFX7 has been implicated in organismal development [7], neurological disorders [8,9,10,11], metabolic disorders [12], and immune cell maintenance [13].The regulatory factor X (RFX) transcription factor family is evolutionarily conserved in the eukaryotic kingdom [14, 15].

。除癌症外，RFX7还与机体发育、神经系统疾病、代谢紊乱和免疫细胞维持有关。调节因子X（RFX）转录因子家族在真核生物界是进化保守的[14，15]。

In humans, the RFX family consists of eight members, all of which possess a conserved winged-helix DNA-binding domain (DBD) through which they can bind cis-regulatory X-box DNA motifs [16, 17]. Most RFX genes show cell type-specific expression, but RFX1, RFX5, and RFX7 are expressed in essentially all tissues [17, 18].

在人类中，RFX家族由八个成员组成，所有成员都具有保守的翼螺旋DNA结合结构域（DBD），通过该结构域，它们可以结合顺式调节X盒DNA基序[16，17]。大多数RFX基因显示细胞类型特异性表达，但RFX1，RFX5和RFX7基本上在所有组织中表达[17，18]。

RFX5 is the phylogenetically closest sibling of RFX7 and the most extensively studied member of the RFX family. RFX5 regulates major histocompatibility complex (MHC) class II genes. Together with RFXANK and RFXAP, RFX5 can form the RFX complex that recruits the transcriptional coactivator CIITA to promote MHC class II gene expression [19].

RFX5是RFX7在系统发育上最接近的兄弟姐妹，也是RFX家族研究最广泛的成员。RFX5调节主要组织相容性复合体（MHC）II类基因。RFX5与RFXANK和RFXAP一起可以形成RFX复合物，该复合物募集转录共激活因子CIITA以促进MHC II类基因表达。

Unlike RFX5, its sibling RFX7 is poorly understood.Recently, we found that the tumor suppressor p53 activates RFX7 upon p53-activating stress signals [6, 20]. We have also identified genes directly and indirectly regulated by RFX7 genome-wide, including genes involved in neuronal processes, metabolic regulation, and t.

与RFX5不同，人们对其兄弟RFX7知之甚少。最近，我们发现肿瘤抑制因子p53在p53激活应激信号时激活RFX7[6，20]。我们还鉴定了由RFX7全基因组直接和间接调控的基因，包括涉及神经元过程，代谢调控和t的基因。

ANKRA2 is a direct p53 targetInterestingly, ANKRA2 has been identified as a potential p53 target gene [29,30,31,32], whereas RFXANK expression does not appear to be induced by p53 signaling [33]. Publicly available data indicate that p53 binds near the TSS of ANKRA2 (Fig. 2a). In agreement with previous data, our ChIP-qPCR data showed inducible p53 binding to the ANKRA2 promoter (Fig.

ANKRA2是一种直接的p53靶向基因，ANKRA2已被确定为潜在的p53靶基因[29，30，31，32]，而RFXANK表达似乎不受p53信号传导的诱导[33]。公开可用的数据表明p53在ANKRA2的TSS附近结合（图2a）。与以前的数据一致，我们的ChIP-qPCR数据显示诱导型p53与ANKRA2启动子结合（图）。

2b), and our RT-qPCR data showed that ANKRA2 mRNA levels increased significantly in response to Nutlin-3a treatment (Fig. 2c). We next sought to test whether ANKRA2 was upregulated through the p53 binding site in its promoter. We cloned the ANKRA2 promoter region and deleted a p53 response element (p53RE) that had been predicted by motif analysis [34].

2b），我们的RT-qPCR数据显示ANKRA2 mRNA水平响应Nutlin-3a处理而显着增加（图2c）。接下来，我们试图测试ANKRA2是否通过其启动子中的p53结合位点上调。我们克隆了ANKRA2启动子区域，并删除了通过基序分析预测的p53反应元件（p53RE）。

Results from dual-luciferase assays showed that the ANKRA2 promoter mediated transcriptional activation upon Nutlin-3a treatment and that this activation was lost when the p53RE was deleted (Fig. 2d). Collectively, these results demonstrate that ANKRA2 is a direct target gene of p53.Fig. 2: ANKRA2 is a direct p53 target gene.a UCSC genome browser image displaying the ANKRA2 gene locus.

双荧光素酶测定的结果表明，在Nutlin-3a处理后，ANKRA2启动子介导了转录激活，并且当删除p53RE时，这种激活就丧失了（图2d）。总的来说，这些结果表明ANKRA2是p53的直接靶基因。图2:ANKRA2是直接的p53靶基因。UCSC基因组浏览器图像显示了ANKRA2基因座。

Publicly available p53 ChIP-seq signals from Nutlin-3a treated U2OS and HCT116 cells [33] and predicted p53 response elements (p53RE) [34] are displayed. b ChIP-qPCR data of p53 binding to the promoters of ANKRA2 and GAPDH negative control. Mean and standard deviation are displayed. Statistical significance was obtained through a two-sided unpaired t-test, n = 3 technical replicates.

显示了来自Nutlin-3a处理的U2OS和HCT116细胞（33）和预测的p53反应元件（p53RE）的公开可用的p53 ChIP-seq信号。b p53与ANKRA2和GAPDH阴性对照启动子结合的ChIP-qPCR数据。显示平均值和标准偏差。通过双侧不成对t检验获得统计学显着性，n=3个技术重复。

c RT-qPCR data of ANKRA2 in U2OS, HCT116, and RPE1 cells. Normalized to ACTR10 negative control and DMSO samples. MDM2 serves as a positive control for p53 induction by Nutlin-3a. Mean and standard deviation are displayed. Statistical significance was obtained through a two-sided .

c U2OS，HCT116和RPE1细胞中ANKRA2的RT-qPCR数据。标准化为ACTR10阴性对照和DMSO样品。MDM2作为Nutlin-3a诱导p53的阳性对照。显示平均值和标准偏差。通过双面获得统计学显着性。

Data availability

数据可用性

The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE [42] partner repository with the dataset identifier PXD020932. RNA sequencing data is accessible through GEO [43] series accession numbers GSE162161 and GSE162162.

质谱蛋白质组学数据已通过PRIDE（42）合作伙伴存储库保存到ProteomeXchange Consortium，数据集标识符为PXD020932。。

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Download referencesAcknowledgementsWe gratefully acknowledge the FLI Core Facilities Next Generation Sequencing (Ivonne Görlich and Cornelia Luge) and Proteomics (Norman Rahnis, Erika K. Sacramento, and Emilio Ciri) for their technical support. We thank Bernhard Schlott for the kind gift of p53 antibody.

。我们感谢Bernhard Schlott提供p53抗体的礼物。

This work was supported by the German Research Foundation (DFG) [research grant FI 1993/2-1 and FI 1993/7-1 to M.F.] and the German Federal Ministry for Education and Research (BMBF) [031L016D to S.H.]. Funding for open access charge: Leibniz Institute on Aging—Fritz Lipmann Institute (FLI). The FLI is a member of the Leibniz Association and is financially supported by the Federal Government of Germany and the State of Thuringia.FundingOpen Access funding enabled and organized by Projekt DEAL.Author informationAuthors and AffiliationsComputational Biology Group, Leibniz Institute on Aging—Fritz Lipmann Institute (FLI), Jena, GermanyKatjana Schwab, Konstantin Riege, Luis Coronel, Silke Förste, Steve Hoffmann & Martin FischerKlinik für Innere Medizin II, Jena University Hospital, Comprehensive Cancer Center Central Germany, Jena, GermanyClara StankoInstitute of Molecular Cell Biology, Center for Molecular Biomedicine Jena (CMB), Jena University Hospital, Jena, GermanyClara StankoAuthorsKatjana SchwabView author publicationsYou can also search for this author in.

。开放获取费用的资金来源：莱布尼茨老龄化研究所弗里茨·利普曼研究所（FLI）。FLI是莱布尼茨协会的成员，由德国联邦政府和图林根州提供财政支持。资金开放获取资金由Projekt交易启用和组织。作者信息作者和附属机构计算生物学组，莱布尼茨老龄化研究所弗里茨·利普曼研究所（FLI），耶拿，德国斯坦贾纳·施瓦布，康斯坦丁·里格，路易斯·科罗内尔，西尔克·福斯特，史蒂夫·霍夫曼和马丁·菲舍克林尼克·弗内尔·梅迪津II，耶拿大学医院，德国中部综合癌症中心，耶拿，德国斯坦科拉分子细胞生物学研究所，耶拿分子生物医学中心（CMB），耶拿大学医院，耶拿也可以在中搜索此作者。

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PubMed Google ScholarContributionsMF conceived the study. MF and SH supervised the work. MF designed the experiments. KS, LC, CS, and SF performed the experiments. KR and MF performed the computational analyses. MF, KS, and SH interpreted the data. MF wrote the manuscript with the help of SH and KS.

PubMed谷歌学术贡献SMF构思了这项研究。MF和SH监督了这项工作。MF设计了实验。KS，LC，CS和SF进行了实验。KR和MF进行了计算分析。MF，KS和SH解释了数据。MF在SH和KS的帮助下撰写了手稿。

All authors read and approved the manuscript.Corresponding authorsCorrespondence to.

所有作者都阅读并批准了手稿。通讯作者通讯。

Steve Hoffmann or Martin Fischer.Ethics declarations

。道德宣言

Competing interests

相互竞争的利益

The authors declare no competing interests.

作者声明没有利益冲突。

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Reprints and permissionsAbout this articleCite this articleSchwab, K., Riege, K., Coronel, L. et al. p53 target ANKRA2 cooperates with RFX7 to regulate tumor suppressor genes.

转载和许可本文引用本文Schwab，K.，Riege，K.，Coronel，L。等人。p53靶标ANKRA2与RFX7合作调节肿瘤抑制基因。

Cell Death Discov. 10, 376 (2024). https://doi.org/10.1038/s41420-024-02149-2Download citationReceived: 04 May 2024Revised: 07 August 2024Accepted: 14 August 2024Published: 24 August 2024DOI: https://doi.org/10.1038/s41420-024-02149-2Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

细胞死亡发现。10376（2024）。https://doi.org/10.1038/s41420-024-02149-2Download引文接收日期：2024年5月4日修订日期：2024年8月7日接受日期：2024年8月14日发布日期：2024年8月24日OI：https://doi.org/10.1038/s41420-024-02149-2Share本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。复制到剪贴板。

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