Hypoxia-induced circSTT3A enhances serine synthesis and promotes H3K4me3 modification to facilitate breast cancer stem cell formation

作者全名："Xu, Ming; Liu, Xiaoqi; Zhou, Xinyue; Qin, Yilu; Yang, Liping; Wen, Siyang; Qiu, Yuxiang; Chen, Shanchun; Tang, Rui; Guo, Yuetong; Liu, Manran; Sun, Yan"

作者地址："[Xu, Ming; Zhou, Xinyue; Qiu, Yuxiang; Chen, Shanchun; Tang, Rui; Guo, Yuetong; Liu, Manran] Chongqing Med Univ, Chinese Minist Educ, Key Lab Lab Med Diagnost, Chongqing 400016, Peoples R China; [Liu, Xiaoqi] Chongqing Med Univ, Childrens Hosp, Pediat Res Inst, Minist Educ,Key Lab Child Dev & Disorders,Chongqi, Chongqing 400014, Peoples R China; [Qin, Yilu] Chongqing Hosp Tradit Chinese Med, Chongqing Key Lab Sichuan Chongqing Coconstruct Di, Chongqing 400021, Peoples R China; [Yang, Liping; Wen, Siyang] Chongqing Med Univ, Affiliated Hosp 2, Dept Lab Med, Chongqing 400010, Peoples R China; [Sun, Yan] Chongqing Med Univ, Basic Med Sch, Dept Cell Biol & Med Genet, Chongqing 400016, Peoples R China; [Sun, Yan] Chongqing Med Univ, Basic Med Sch, Dept Cell Biol & Med Genet, 1 Yi Xue Yuan Rd, Chongqing 400016, Peoples R China"

通信作者："Sun, Y (通讯作者)，Chongqing Med Univ, Basic Med Sch, Dept Cell Biol & Med Genet, 1 Yi Xue Yuan Rd, Chongqing 400016, Peoples R China."

来源：PHARMACOLOGICAL RESEARCH

ESI学科分类：PHARMACOLOGY & TOXICOLOGY

WOS号：WOS:001102985300001

JCR分区：Q1

影响因子：9.1

年份：2023

卷号：197

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：Breast cancer; CircSTT3A; PGK1; Serine metabolism; Chemotherapy resistance

摘要："Hypoxia is a key feature of tumor microenvironment that contributes to the development of breast cancer stem cells (BCSCs) with strong self-renewal properties. However, the specific mechanism underlying hypoxia in BCSC induction is not completely understood. Herein, we provide evidence that a novel hypoxia-specific circSTT3A is significantly upregulated in clinical breast cancer (BC) tissues, and is closely related to the clinical stage and poor prognosis of patients with BC. The study revealed that hypoxia-inducible factor 1 alpha (HIF1 alpha)-regulated circSTT3A has a remarkable effect on mammosphere formation in breast cancer cells. Mechanistically, circSTT3A directly interacts with nucleotide-binding domain of heat shock protein 70 (HSP70), thereby facilitating the recruitment of phosphoglycerate kinase 1 (PGK1) via its substrate-binding domain, which reduces the ubiquitination and increases the stability of PGK1. The enhanced levels of PGK1 catalyze 1,3-diphosphoglycerate (1,3-BPG) into 3-phosphoglycerate (3-PG) leading to 3-PG accumulation and increased serine synthesis, S-adenosylmethionine (SAM) accumulation, and trimethylation of histone H3 lysine 4 (H3K4me3). The activation of the H3K4me3 contributes to BCSCs by increasing the transcriptional level of stemness-related factors. Especially, our work reveals that either loss of circSTT3A or PGK1 substantially suppresses tumor initiation and tumor growth, which dramatically increases the sensitivity of tumors to doxorubicin (DOX) in mice. Injection of PGK1-silenced spheroids with 3-PG can significantly reverse tumor initiation and growth in mice, thereby increasing tumor resistance to DOX. In conclusion, our study sheds light on the functional role of hypoxia in the maintenance of BCSCs via circSTT3A/HSP70/PGK1-mediated serine synthesis, which provides new insights into metabolic reprogramming, tumor initiation and growth. Our findings suggest that targeting circSTT3A alone or in combination with chemotherapy has potential clinical value for BC management."

基金机构：National Natural Science Foundation of China (NSFC); Program for Youth Innovation in Future Medicine of Chongqing Medical University [81874199]; Chongqing Medical University [31671481]; [W0068]; [BJRC202126]

基金资助正文："This work was supported in part by National Natural Science Foundation of China (NSFC 81874199, and NSFC 31671481) for Manran Liu. And also supported in part by the Program for Youth Innovation in Future Medicine of Chongqing Medical University (W0068) for Yan Sun, and outstanding Postgraduate Fund of Chongqing Medical University (BJRC202126) for Ming Xu."