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<p>Cisplatin resistance remains a major challenge in the clinical treatment of bladder cancer (BC), and the epigenetic regulation of this resistance, particularly involving 5-hydroxymethylcytosine (5hmC), has not been fully elucidated. Here, we investigated the role of 5hmC and vitamin C (VC) in modulating cisplatin sensitivity in BC. Clinical analyses of 36 BC patients receiving cisplatin-based neoadjuvant chemotherapy showed that reduced 5hmC levels in pre-chemotherapy tumor tissues were significantly associated with cisplatin resistance (CR-BC) and poor prognosis, with low 5hmC correlating with shorter progression-free survival (PFS). In vitro, we established two cisplatin-resistant cell lines (T24-CR, UMUC-3-CR) that exhibited reduced 5hmC compared to parental cells. Treatment with 100&#xa0;μM VC significantly restored 5hmC levels in CR-BC cells by activating <i>TET</i> enzymes, inhibited cell proliferation, and enhanced cisplatin sensitivity; these effects were abrogated by the <i>TET</i> inhibitor Bobcat339, confirming VC acts in a <i>TET</i>-dependent manner. Mechanistically, genome-wide 850&#xa0;K methylation array and RNA-seq analyses revealed that VC upregulated methylation specifically at the promoter of <i>ATF4</i>, a downstream effector of the MAPK pathway, thereby downregulating <i>ATF4</i> expression. <i>ATF4</i> knockdown in CR-BC cells increasing cisplatin sensitivity, while Bobcat339 reversed VC-induced <i>ATF4</i> downregulation. In vivo, VC combined with cisplatin significantly inhibited tumor growth in T24-CR xenografts, and co-treatment with <i>ATF4</i> knockdown further enhanced this effect, accompanied by elevated 5hmC and reduced <i>Ki67</i> in tumors. Collectively, our findings identify reduced 5hmC as a hallmark of cisplatin-resistant BC and reveal a novel mechanism by which VC enhances cisplatin sensitivity. VC activates <i>TET</i> enzymes to increase 5mC at the <i>ATF4</i> promoter, downregulating <i>ATF4</i> and modulating the MAPK pathway. This highlights VC as a potential epigenetic adjuvant to overcome cisplatin resistance in BC.</p>

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Vitamin C enhances cisplatin sensitivity in bladder cancer via 5hmC-mediated epigenetic modulation of ATF4

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月19日

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  • Chunru Xu,
  • Wenwei Ying,
  • Yuhui He,
  • Yucai Wu,
  • Tai Tian,
  • Jilong Zhang,
  • Shiming He,
  • Cuijian Zhang,
  • Xuesong Li,
  • Yanqing Gong

摘要

Cisplatin resistance remains a major challenge in the clinical treatment of bladder cancer (BC), and the epigenetic regulation of this resistance, particularly involving 5-hydroxymethylcytosine (5hmC), has not been fully elucidated. Here, we investigated the role of 5hmC and vitamin C (VC) in modulating cisplatin sensitivity in BC. Clinical analyses of 36 BC patients receiving cisplatin-based neoadjuvant chemotherapy showed that reduced 5hmC levels in pre-chemotherapy tumor tissues were significantly associated with cisplatin resistance (CR-BC) and poor prognosis, with low 5hmC correlating with shorter progression-free survival (PFS). In vitro, we established two cisplatin-resistant cell lines (T24-CR, UMUC-3-CR) that exhibited reduced 5hmC compared to parental cells. Treatment with 100 μM VC significantly restored 5hmC levels in CR-BC cells by activating TET enzymes, inhibited cell proliferation, and enhanced cisplatin sensitivity; these effects were abrogated by the TET inhibitor Bobcat339, confirming VC acts in a TET-dependent manner. Mechanistically, genome-wide 850 K methylation array and RNA-seq analyses revealed that VC upregulated methylation specifically at the promoter of ATF4, a downstream effector of the MAPK pathway, thereby downregulating ATF4 expression. ATF4 knockdown in CR-BC cells increasing cisplatin sensitivity, while Bobcat339 reversed VC-induced ATF4 downregulation. In vivo, VC combined with cisplatin significantly inhibited tumor growth in T24-CR xenografts, and co-treatment with ATF4 knockdown further enhanced this effect, accompanied by elevated 5hmC and reduced Ki67 in tumors. Collectively, our findings identify reduced 5hmC as a hallmark of cisplatin-resistant BC and reveal a novel mechanism by which VC enhances cisplatin sensitivity. VC activates TET enzymes to increase 5mC at the ATF4 promoter, downregulating ATF4 and modulating the MAPK pathway. This highlights VC as a potential epigenetic adjuvant to overcome cisplatin resistance in BC.