2. Academic Validation
  3. Hypoxia-induced circSTT3A enhances serine synthesis and promotes H3K4me3 modification to facilitate breast cancer stem cell formation

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

  • Pharmacol Res. 2023 Oct 20:197:106964. doi: 10.1016/j.phrs.2023.106964.
Ming Xu 1,  Xiaoqi Liu 2,  Xinyue Zhou 1,  Yilu Qin 3,  Liping Yang 4,  Siyang Wen 4,  Yuxiang Qiu 1,  Shanchun Chen 1,  Rui Tang 1,  Yuetong Guo 1,  Manran Liu 1,  Yan Sun 5
Affiliations

Affiliations

  • 1 Key Laboratory of Laboratory Medical Diagnostics, Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, China.
  • 2 Pediatric Research Institute, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing 400014, China.
  • 3 Chongqing Key Laboratory of Sichuan-Chongqing Co-construction for Diagnosis and Treatment of Infectious Diseases Integrated Traditional Chinese and Western Medicine, Chongqing Hospital of Traditional Chinese Medicine, Chongqing 400021, China.
  • 4 Department of Laboratory Medicine, the Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China.
  • 5 Department of Cell Biology and Medical Genetics, Basic Medical School, Chongqing Medical University, Chongqing 400016, China. Electronic address: yansun@cqmu.edu.cn.
PMID: 37865128 DOI: 10.1016/j.phrs.2023.106964
Abstract

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 (HIF1α)-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.

Keywords

Breast cancer; Chemotherapy resistance; CircSTT3A; PGK1; Serine metabolism.

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