2. Academic Validation
  3. Compound AC1Q3QWB upregulates CDKN1A and SOX17 by interrupting the HOTAIR-EZH2 interaction and enhances the efficacy of tazemetostat in endometrial cancer

Compound AC1Q3QWB upregulates CDKN1A and SOX17 by interrupting the HOTAIR-EZH2 interaction and enhances the efficacy of tazemetostat in endometrial cancer

  • Cancer Lett. 2023 Dec 1:578:216445. doi: 10.1016/j.canlet.2023.216445.
Lingli Chen 1,  Xingyu Zheng 1,  Wenlu Liu 1,  Yiqing Sun 1,  Shuangshuang Zhao 1,  Lina Tian 1,  Wenyan Tian 1,  Fengxia Xue 2,  Chunsheng Kang 3,  Yingmei Wang 4
Affiliations

Affiliations

  • 1 Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, Tianjin, 300052, China; Tianjin Key Laboratory of Female Reproductive Health and Eugenics, Tianjin Medical University General Hospital, Tianjin, 300052, China.
  • 2 Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, Tianjin, 300052, China; Tianjin Key Laboratory of Female Reproductive Health and Eugenics, Tianjin Medical University General Hospital, Tianjin, 300052, China. Electronic address: xuefengxia@tmu.edu.cn.
  • 3 Department of Neurosurgery, Tianjin Medical University General Hospital, Lab of Neuro-oncology, Tianjin Neurological Institute, Tianjin, 300052, China. Electronic address: kang97061@tmu.edu.cn.
  • 4 Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, Tianjin, 300052, China; Tianjin Key Laboratory of Female Reproductive Health and Eugenics, Tianjin Medical University General Hospital, Tianjin, 300052, China. Electronic address: wangyingmei@tmu.edu.cn.
PMID: 37866545 DOI: 10.1016/j.canlet.2023.216445
Abstract

Endometrial Cancer (EC) is a common malignancy of the female reproductive system, with an escalating incidence. Recurrent/metastatic EC presents a poor prognosis. The interaction between the long non-coding RNA (lncRNA) HOTAIR and the polycomb repressive complex 2 (PRC2) induces abnormal silencing of tumor suppressor genes, exerting a pivotal role in tumorigenesis. We have previously discovered AC1Q3QWB (AQB), a small-molecule compound targeting HOTAIR-EZH2 interaction. In the present study, we unveil that AQB selectively hampers the interaction between HOTAIR and EZH2 within EC cells, thus reversing the epigenetic suppression of tumor suppressor genes. Furthermore, our findings demonstrate AQB's synergistic effect with tazemetostat (TAZ), an EZH2 Inhibitor, significantly boosting the expression of CDKN1A and SOX17. This, in turn, induces cell cycle arrest and impedes EC cell proliferation, migration, and invasion. In vivo experiments further validate AQB's potential by enhancing TAZ's anti-tumor efficacy at lower doses. Our results advocate AQB, a recently discovered small-molecule inhibitor, as a promising agent against EC cells. When combined with TAZ, it offers a novel therapeutic strategy for EC treatment.

Keywords

AQB; CDKN1A; Endometrial cancer; SOX17; Small-molecule inhibitor.

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