Chen Lingli, Zheng Xingyu, Liu Wenlu, Sun Yiqing, Zhao Shuangshuang, Tian Lina, Tian Wenyan, Xue Fengxia, Kang Chunsheng, Wang Yingmei
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.
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.
Cancer Lett. 2023 Dec 1;578:216445. doi: 10.1016/j.canlet.2023.216445. Epub 2023 Oct 20.
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.
子宫内膜癌（EC）是女性生殖系统常见的恶性肿瘤，其发病率呈上升趋势。复发性/转移性EC预后较差。长链非编码RNA（lncRNA）HOTAIR与多梳抑制复合物2（PRC2）之间的相互作用会导致肿瘤抑制基因异常沉默，在肿瘤发生中起关键作用。我们之前发现了AC1Q3QWB（AQB），一种靶向HOTAIR-EZH2相互作用的小分子化合物。在本研究中，我们揭示AQB可选择性地阻碍EC细胞内HOTAIR与EZH2之间的相互作用，从而逆转肿瘤抑制基因的表观遗传抑制。此外，我们的研究结果表明AQB与EZH2抑制剂他泽司他（TAZ）具有协同作用，可显著提高CDKN1A和SOX17的表达。这进而诱导细胞周期停滞，并阻碍EC细胞的增殖、迁移和侵袭。体内实验通过在较低剂量下增强TAZ的抗肿瘤疗效进一步验证了AQB的潜力。我们的结果支持AQB，一种最近发现的小分子抑制剂，作为一种有前景的抗EC细胞药物。与TAZ联合使用时，它为EC治疗提供了一种新的治疗策略。
