NAT10 inhibition promotes ac4C-dependent ferroptosis to counteract sorafenib resistance in nasopharyngeal carcinoma

IF 4.5 2区医学 Q1 ONCOLOGY Cancer Science Pub Date : 2024-07-22 DOI:10.1111/cas.16249

Ziyi Xue, Haijing Xie, Ying Shan, Lin Zhang, Lin Cheng, Wenyue Chen, Rui Zhu, Kaiwen Zhang, Haosheng Ni, Zhenxin Zhang, Yiwen You, Bo You

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Abstract

Sorafenib, an anticancer drug, has been shown to induce ferroptosis in cancer cells. However, resistance to sorafenib greatly limits its therapeutic efficacy, and the exact mechanism of resistance is not fully understood. This study investigated the role of N-Acetyltransferase 10 (NAT10) in influencing the anticancer activity of sorafenib in nasopharyngeal carcinoma (NPC) and its molecular mechanism. NAT10 expression was significantly upregulated in NPC. Mechanistically, NAT10 promotes proteins of solute carrier family 7 member 11 (SLC7A11) expression through ac4C acetylation, inhibiting sorafenib-induced ferroptosis in NPC cells. The combined application of sorafenib and the NAT10 inhibitor remodelin significantly inhibits SLC7A11 expression and promotes ferroptosis in NPC cells. In vivo knockout of NAT10 inhibited the growth of sorafenib-resistant NPC. Our findings suggest that NAT10 inhibition might be a promising therapeutic approach to enhance the anticancer activity of sorafenib.

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抑制NAT10可促进ac4C依赖性铁氧化，从而抵消鼻咽癌患者对索拉非尼的耐药性。

索拉非尼（Sorafenib）是一种抗癌药物，已被证明能诱导癌细胞发生铁变态反应。然而，索拉非尼的耐药性极大地限制了其疗效，而耐药性的确切机制尚未完全明了。本研究探讨了N-乙酰转移酶10（NAT10）在鼻咽癌中影响索拉非尼抗癌活性的作用及其分子机制。NAT10在鼻咽癌中表达明显上调。从机理上讲，NAT10通过ac4C乙酰化促进溶质运载家族7成员11（SLC7A11）蛋白的表达，从而抑制索拉非尼诱导的鼻咽癌细胞铁变态反应。索拉非尼和NAT10抑制剂remodelin的联合应用能显著抑制SLC7A11的表达，并促进鼻咽癌细胞的铁沉降。体内敲除NAT10抑制了索拉非尼耐药的鼻咽癌细胞的生长。我们的研究结果表明，抑制NAT10可能是增强索拉非尼抗癌活性的一种有前途的治疗方法。

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来源期刊

Cancer Science 医学-肿瘤学

自引率

3.50%

发文量

406

审稿时长

2 months

期刊介绍： Cancer Science (formerly Japanese Journal of Cancer Research) is a monthly publication of the Japanese Cancer Association. First published in 1907, the Journal continues to publish original articles, editorials, and letters to the editor, describing original research in the fields of basic, translational and clinical cancer research. The Journal also accepts reports and case reports. Cancer Science aims to present highly significant and timely findings that have a significant clinical impact on oncologists or that may alter the disease concept of a tumor. The Journal will not publish case reports that describe a rare tumor or condition without new findings to be added to previous reports; combination of different tumors without new suggestive findings for oncological research; remarkable effect of already known treatments without suggestive data to explain the exceptional result. Review articles may also be published.

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