2. Academic Validation
  3. TFAP2A-mediated downregulation of UBE2C is crucial for endometrial decidualization and embryo implantation

TFAP2A-mediated downregulation of UBE2C is crucial for endometrial decidualization and embryo implantation

  • Cell Signal. 2025 Nov:135:112016. doi: 10.1016/j.cellsig.2025.112016.
Li Yu 1,  Yifan Luo 2,  Yixia Yang 1,  Liqun Lou 2,  Xinbao Zhang 3,  Jiamin Zhu 4,  Yan Zhang 5,  Hong Liao 6,  Mingzhu Bai 7,  Zuoshu Qin 8,  Zhenbo Zhang 9
Affiliations

Affiliations

  • 1 Department of Obstetrics and Gynecology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.
  • 2 Reproductive Medicine Center, Department of Obstetrics and Gynecology, Tongji Hospital, Tongji School of medicine, Tongji University, Shanghai 200065, China.
  • 3 School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China.
  • 4 Department of Obstetrics and Gynecology, Shanghai Baoshan Wusong Center Hospital, Shanghai 200940, China.
  • 5 Department of Gynecology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou 215000, China.
  • 6 Department of Clinical Laboratory Medicine, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 200040, China.
  • 7 Reproductive Medicine Center, Xuzhou Maternity and Child Health Care Hospital, Jiangsu 221009, China; Department of Obstetrics and Gynecology, Zhongda Hospital, Southeast University, Nanjing, China. Electronic address: baimingzhui@sina.cn.
  • 8 Reproductive Medicine Center, Department of Obstetrics and Gynecology, Tongji Hospital, Tongji School of medicine, Tongji University, Shanghai 200065, China. Electronic address: zuoshuqin@tongji.edu.cn.
  • 9 Reproductive Medicine Center, Department of Obstetrics and Gynecology, Tongji Hospital, Tongji School of medicine, Tongji University, Shanghai 200065, China. Electronic address: zhangzhenbozzb@tongji.edu.cn.
PMID: 40701315 DOI: 10.1016/j.cellsig.2025.112016
Abstract

Decidualization triggered by human endometrial stromal cells (HESCs) is a critical step in the establishment of endometrial receptivity, which provides an ideal environment for embryo implantation. However, the specific regulatory networks and core genes involved in the decidualization process remain incompletely characterized. Here, we identified ubiquitin-conjugating enzyme 2C (UBE2C), a key cell cycle regulator, as a pivotal factor in decidualization through comprehensive in vitro and in vivo investigations. RNA Sequencing revealed UBE2C as a potential hub gene in the human endometrium. We found UBE2C expression was significantly downregulated in secretory-phase endometrium and in vitro decidual HESCs. Functional studies demonstrated that UBE2C overexpression attenuated decidual marker expression and disrupted normal proliferation in HESCs, mechanistically linked to NF-κB signaling pathway. Consistent with in vitro findings, mice studies showed UBE2C downregulation in peri-implantation uterine tissue, with uterine-specific UBE2C overexpression impairing both embryo implantation and decidualization. Further mechanistic exploration identified transcription factor AP-2 alpha (TFAP2A) as a novel mediator of UBE2C. Decidual stimulation promoted TFAP2A degradation via the ubiquitination pathway. Clinical relevance was established through the observation of elevated UBE2C and TFAP2A expression in secretory endometrium from recurrent implantation failure (RIF) patients. In conclusion, for endometrial decidualization and embryo implantation, TFAP2A-mediated downregulation of UBE2C is required. Dysregulation of this axis may compromise endometrial receptivity, suggesting UBE2C and TFAP2A as promising therapeutic targets for decidualization-related disorders such as RIF.

Keywords

Decidualization; Embryo implantation; Recurrent implantation failure (RIF); Stromal cells; Transcription factor AP-2 alpha (TFAP2A); Ubiquitin-conjugating enzyme 2C (UBE2C).

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