Scholarlink

Background <p>Mucinous adenocarcinoma (MAC) represents a subtype of colorectal cancer (CRC) characterized by insensitivity to chemoradiotherapy, necessitating urgent development of novel therapeutic strategies specifically targeting tumor biology of MAC.</p> Methods <p>Integrated analysis of ATAC-seq and RNA-seq data was performed to identify pivotal targets mediating treatment resistance in MAC. Subsequently, clinical specimens were collected for immunohistochemistry, RT-qPCR, and Kaplan–Meier survival analysis. Functional validation of the target was conducted through in vitro experiments encompassing colony formation, drug sensitivity assessments, synergy testing, and immunofluorescence. The translational potential of the target was evaluated in vivo.</p> Results <p>Integrated ATAC-seq and RNA-seq analyses identified hypoxia and dysregulated ferroptosis as critical features of MAC, screening carbonic anhydrase 9 (CA9) as a pivotal gene implicated in MAC treatment resistance. CA9-specific inhibitor synergized with 5-fluorouracil to exert enhanced antitumor effects. Additionally, CA9 knockdown or inhibition arrested tumor cell proliferation and migration, promoted intracellular reactive oxygen species generation, induced mitochondrial shrinkage, increased mitochondrial iron content, reduced glutathione levels, and triggered lipid peroxidation. Inhibitors of either ferroptosis or apoptosis antagonized CA9 inhibitor-mediated cell death. In vivo experiments demonstrated that CA9 knockdown or inhibition significantly delayed tumor growth. Co-immunoprecipitation revealed that CA9 interacts directly or indirectly with multiple ferroptosis-associated proteins.</p> Conclusion <p>This study identifies the hypoxic tumor microenvironments and dysregulated ferroptosis as pivotal molecular characteristics of MAC, and proposes a novel mechanism underlying treatment resistance in MAC: Hypoxia remodels chromatin accessibility through epigenetic modifications, to dysregulate CA9 expression, which may subsequently modulate cellular susceptibility to ferroptosis, culminating in treatment resistance, and targeting CA9 may improve the therapeutic efficacy of MAC, although further studies are needed to establish direct causality.</p> Graphical abstract <p>Hypoxia remodels chromatin accessibility through epigenetic modifications, to dysregulate CA9 expression, which subsequently modulates cellular susceptibility to ferroptosis, apoptosis, and autophagy, culminating in treatment resistance.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Hypoxia-mediated chromatin accessibility reprogramming of CA9 induces treatment resistance in colorectal mucinous adenocarcinoma

  • 期刊论文

  • 发表日期：

    2026年6月24日

查看全文
  • An Huang,
  • Haopeng Hong,
  • Zhuang Sun,
  • Zhaoya Gao,
  • Yong Yang,
  • Jiajia Chen,
  • Yonghui Sun,
  • Zhengrong Li,
  • Ming Li,
  • Jin Gu

摘要

Background

Mucinous adenocarcinoma (MAC) represents a subtype of colorectal cancer (CRC) characterized by insensitivity to chemoradiotherapy, necessitating urgent development of novel therapeutic strategies specifically targeting tumor biology of MAC.

Methods

Integrated analysis of ATAC-seq and RNA-seq data was performed to identify pivotal targets mediating treatment resistance in MAC. Subsequently, clinical specimens were collected for immunohistochemistry, RT-qPCR, and Kaplan–Meier survival analysis. Functional validation of the target was conducted through in vitro experiments encompassing colony formation, drug sensitivity assessments, synergy testing, and immunofluorescence. The translational potential of the target was evaluated in vivo.

Results

Integrated ATAC-seq and RNA-seq analyses identified hypoxia and dysregulated ferroptosis as critical features of MAC, screening carbonic anhydrase 9 (CA9) as a pivotal gene implicated in MAC treatment resistance. CA9-specific inhibitor synergized with 5-fluorouracil to exert enhanced antitumor effects. Additionally, CA9 knockdown or inhibition arrested tumor cell proliferation and migration, promoted intracellular reactive oxygen species generation, induced mitochondrial shrinkage, increased mitochondrial iron content, reduced glutathione levels, and triggered lipid peroxidation. Inhibitors of either ferroptosis or apoptosis antagonized CA9 inhibitor-mediated cell death. In vivo experiments demonstrated that CA9 knockdown or inhibition significantly delayed tumor growth. Co-immunoprecipitation revealed that CA9 interacts directly or indirectly with multiple ferroptosis-associated proteins.

Conclusion

This study identifies the hypoxic tumor microenvironments and dysregulated ferroptosis as pivotal molecular characteristics of MAC, and proposes a novel mechanism underlying treatment resistance in MAC: Hypoxia remodels chromatin accessibility through epigenetic modifications, to dysregulate CA9 expression, which may subsequently modulate cellular susceptibility to ferroptosis, culminating in treatment resistance, and targeting CA9 may improve the therapeutic efficacy of MAC, although further studies are needed to establish direct causality.

Graphical abstract

Hypoxia remodels chromatin accessibility through epigenetic modifications, to dysregulate CA9 expression, which subsequently modulates cellular susceptibility to ferroptosis, apoptosis, and autophagy, culminating in treatment resistance.