AbstractEsophageal squamous cell carcinoma (ESCC) possesses a poor prognosis and treatment outcome. Dysregulated metabolism contributes to unrestricted growth of multiple cancers. However, abnormal metabolism, such as highly activated pentose phosphate pathway (PPP) in the progression of ESCC remains largely unknown.

摘要食管鳞状细胞癌（ESCC）预后不良，治疗效果不佳。代谢失调导致多种癌症的无限制生长。然而，ESCC进展中的异常代谢，例如高度活化的戊糖磷酸途径（PPP）仍然未知。

Herein, we report that high-mobility group AT-hook 1 (HMGA1), a structural transcriptional factor involved in chromatin remodeling, promoted the development of ESCC by upregulating the PPP. We found that HMGA1 was highly expressed in ESCC. Elevated HMGA1 promoted the malignant phenotype of ESCC cells.

在这里，我们报告说，高迁移率族AT钩1（HMGA1）是一种参与染色质重塑的结构转录因子，通过上调PPP促进ESCC的发展。我们发现HMGA1在ESCC中高度表达。HMGA1升高促进了ESCC细胞的恶性表型。

Conditional knockout of HMGA1 markedly reduced 4-nitroquinoline-1-oxide (4NQO)-induced esophageal tumorigenesis in mice. Through the metabolomic analysis and the validation assay, we found that HMGA1 upregulated the non-oxidative PPP. With the transcriptome sequencing, we identified that HMGA1 upregulated the expression of transketolase (TKT), which catalyzes the reversible reaction in non-oxidative PPP to exchange metabolites with glycolytic pathway.

HMGA1的条件性敲除显着降低了4-硝基喹啉-1-氧化物（4NQO）诱导的小鼠食管肿瘤发生。。通过转录组测序，我们发现HMGA1上调了转酮醇酶（TKT）的表达，该酶催化非氧化PPP中的可逆反应，以与糖酵解途径交换代谢物。

HMGA1 knockdown suppressed the PPP by downregulating TKT, resulting in the reduction of nucleotides in ESCC cells. Overexpression of HMGA1 upregulated PPP and promoted the survival of ESCC cells by activating TKT. We further characterized that HMGA1 promoted the transcription of TKT by interacting with and enhancing the binding of transcription factor SP1 to the promoter of TKT.

。HMGA1的过表达通过激活TKT上调PPP并促进ESCC细胞的存活。我们进一步表征了HMGA1通过与转录因子SP1相互作用并增强其与TKT启动子的结合来促进TKT的转录。

Therapeutics targeting TKT with an inhibitor, oxythiamine, reduced HMGA1-induced ESCC cell proliferation and tumor growth. Together, in this study, we identified a new role of HMGA1 in ESCCs by upregulating TKT-mediated activation of PPP. Our results provided a new insight into the role of HMGA1/TKT/PPP in ESCC tumorigenesis and targeted .

用抑制剂oxythiamine靶向TKT的治疗剂可减少HMGA1诱导的ESCC细胞增殖和肿瘤生长。总之，在这项研究中，我们通过上调TKT介导的PPP激活，确定了HMGA1在ESCC中的新作用。我们的结果为HMGA1/TKT/PPP在ESCC肿瘤发生和靶向中的作用提供了新的见解。

IntroductionEsophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) are two major subtypes of esophageal cancer. The 5-year survival rate of esophageal cancer is less than 20%, which is mainly caused by the inability to diagnose at the early stage, high invasiveness of the tumor, and lacking of effective treatments [1,2,3,4].

简介食管鳞状细胞癌（ESCC）和食管腺癌（EAC）是食管癌的两种主要亚型。食管癌的5年生存率低于20%，这主要是由于无法在早期诊断，肿瘤的高侵袭性以及缺乏有效的治疗[1,2,3,4]。

There is an urgent need to find effective molecular targets for the treatment of esophageal cancer.Metabolomics has become a new platform for biomarker discovery [5, 6]. Cell bioenergetics abnormality is a hallmark of cancer [7, 8]. To support tumor growth, cancer cells make a variety of metabolic adaptations.

。代谢组学已成为生物标志物发现的新平台[5，6]。细胞生物能量异常是癌症的标志[7，8]。为了支持肿瘤生长，癌细胞进行各种代谢适应。

Metabolites not only act as substrates for the generation of bioenergetics, but also regulate biomass synthesis and gene expression of cancer cells [9]. For example, pentose phosphate pathway (PPP) generates pentose phosphate, such as ribose 5-phosphate (R5P), to provide substrates for nucleic acid synthesis and NADPH and GSH for the removal of reactive oxygen species (ROS) and generation of fatty acid within cells [10,11,12,13].

代谢物不仅作为生物能量产生的底物，而且调节癌细胞的生物量合成和基因表达。例如，磷酸戊糖途径（PPP）产生磷酸戊糖，如核糖5-磷酸（R5P），为核酸合成和NADPH和GSH提供底物，用于去除活性氧（ROS）和细胞内脂肪酸的产生[10,11,12,13]。

Thus, PPP plays a key role in meeting the needs of cancer cells for anabolism and resisting oxidative stress. Cancer cells directly or indirectly increase glucose flux to PPP [14]. Elevated PPP in cancer cells may thus distinguish them from normal cells. Targeting PPP could be a promising option for cancer treatment.PPP is regulated by a variety of factors, such as tumor suppressors, oncoproteins, and intracellular metabolites [15].

因此，PPP在满足癌细胞合成代谢和抵抗氧化应激的需求方面起着关键作用。癌细胞直接或间接增加葡萄糖通量至PPP（14）。因此，癌细胞中PPP升高可能使其与正常细胞区分开。靶向PPP可能是癌症治疗的有希望的选择。。

Glucose-6-phosphate (G6P) dehydrogenase (G6PD) is a rate-limiting enzyme in oxidative PPP and determines the flux of G6P into the pathway [16, 17]. The transketolase (TKT) is a key enzyme in non-oxidative PPP [18, 19] and bidirectionally regulates carbon flux between.

葡萄糖-6-磷酸脱氢酶（G6P）是氧化PPP中的限速酶，决定了G6P进入途径的通量[16，17]。转酮酶（TKT）是非氧化PPP中的关键酶[18，19]，并双向调节碳通量。

Data availability

数据可用性

The authors declare that all the data supporting our findings in the study are available within the paper.

作者声明，论文中提供了支持我们研究结果的所有数据。

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Download referencesAcknowledgementsWe would like to thank scientists in the Xu laboratory for their helpful discussion and support. This work was supported by the National Key Research and Development Program of China (2023YFE0109800), the National Natural Science Foundation of China (Nos.

下载参考文献致谢我们要感谢Xu实验室的科学家们的有益讨论和支持。这项工作得到了国家重点研究发展计划（2023YFE0109800），国家自然科学基金（No。

82020108024 and 82200596), and the China Postdoctoral Science Foundation (No. 2022M721014).FundingThis work was supported by the National Key Research and Development Program of China (2023YFE0109800), the National Natural Science Foundation of China (Nos. 82020108024 and 82200596), and the China Postdoctoral Science Foundation (No.

82020108024和82200596）以及中国博士后科学基金会（编号2022M721014）。资助这项工作得到了国家重点研究发展计划（2023YFE0109800），国家自然科学基金（82020108024和82200596号）和中国博士后科学基金（No。

2022M721014).Author informationAuthor notesThese authors contributed equally: Meng-Jie Liu, Yuan Zhao, Qiu-Tong Li.Authors and AffiliationsSchool of Life Sciences, Henan University, Kaifeng, Henan Province, ChinaMeng-Jie Liu, Yuan Zhao, Qiu-Tong Li, Xin-Yuan Lei, Kai-Yue He, Jin-Rong Guo, Jing-Yu Yang, Zhen-Hua Yan, Dan-Hui Wu, Lei Zhang, Yong-Ping Jian & Zhi-Xiang XuAuthorsMeng-Jie LiuView author publicationsYou can also search for this author in.

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PubMed Google ScholarContributionsMJL designed the study, performed the experiments, and wrote the manuscript. YZ, QTL, XYL, KYH, JRG, JYY, ZHY, DHW, and LZ performed the experiments. ZXX and YPJ contributed to the conception and writing. All authors read and approved the final manuscript.Corresponding authorsCorrespondence to.

PubMed Google ScholarContributionsMJL设计了这项研究，进行了实验，并撰写了手稿。YZ，QTL，XYL，KYH，JRG，JYY，ZHY，DHW和LZ进行了实验。ZXX和YPJ为构思和写作做出了贡献。所有作者都阅读并批准了最终稿件。通讯作者通讯。

Yong-Ping Jian or Zhi-Xiang Xu.Ethics declarations

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Competing interests

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Protocols for animal usage were approved by the institutional animal care and use committee (IACUC) at Henan University, China. All animal experiments were conducted on the basis of the institutional guidelines, and were approved by the Laboratory Animal Center of Henan University.

动物使用方案已获得中国河南大学机构动物护理和使用委员会（IACUC）的批准。所有动物实验均根据机构指南进行，并经河南大学实验动物中心批准。

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Reprints and permissionsAbout this articleCite this articleLiu, MJ., Zhao, Y., Li, QT. et al. HMGA1 promotes the progression of esophageal squamous cell carcinoma by elevating TKT-mediated upregulation of pentose phosphate pathway.

转载和许可本文引用本文Liu，MJ。，赵，李，QT。HMGA1通过提高TKT介导的戊糖磷酸途径的上调来促进食管鳞状细胞癌的进展。

Cell Death Dis 15, 541 (2024). https://doi.org/10.1038/s41419-024-06933-xDownload citationReceived: 27 August 2023Revised: 18 July 2024Accepted: 22 July 2024Published: 30 July 2024DOI: https://doi.org/10.1038/s41419-024-06933-xShare 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Dis 15541（2024）。https://doi.org/10.1038/s41419-024-06933-xDownload引文接收日期：2023年8月27日修订日期：2024年7月18日接受日期：2024年7月22日发布日期：2024年7月30日OI：https://doi.org/10.1038/s41419-024-06933-xShare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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