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<p>HECT and RCC1-like domain-containing protein 1 (HERC1), a large E3 ubiquitin ligase, has been implicated in neural development and genome stability, but its role in cancer remains unclear. This study identifies HERC1 as a critical regulator of cancer stemness, metastasis, and chemoresistance in head and neck squamous cell carcinoma (HNSCC). CD44⁺ HNSCC organoids with shRNA-mediated HERC1 knockdown were assessed for stemness, EMT, and IL-6/STAT3/HERC1 signaling using molecular assays, CAF co-culture, xenografts, and tissue immunohistochemistry. High HERC1 expression in TCGA-HNSCC datasets was associated with enrichment of stemness signatures. HERC1 knockdown in CD44⁺ cells reduced Sox2, and Slug expression, suppressed EMT, and impaired metastatic potential in Transwell assays and in vivo models. CD44⁺ cells formed organoids in a HERC1-dependent manner. CAF co-culture showed that IL-6 promoted organoid invasiveness through STAT3 activation and HERC1 upregulation. Mechanistic validation revealed that HERC1 modulation altered p-STAT3, p-ERK, CD44, and Slug levels, and STAT3 inhibition reduced HERC1 expression, defining a p-STAT3–HERC1–p-ERK axis. IL-6 neutralization or HERC1 inhibition sensitized organoids to 5-fluorouracil and cisplatin, and combined HERC1 knockdown with 5-FU markedly reduced tumor growth and increased apoptosis. Tissue arrays confirmed elevated HERC1 and pathway markers in advanced HNSCC. These findings define an p-STAT3–HERC1–p-ERK signaling axis that promotes cancer stemness and chemoresistance through CD44<sup>+</sup> tumor–stromal crosstalk. Targeting HERC1 may offer a promising strategy to eliminate cancer stem-like cells in HNSCC.</p>

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HERC1 oncogene enhances stemness and tumorigenic potential in CD44+-derived organoids of head and neck squamous cell carcinoma through IL-6/STAT3 signaling

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月11日

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  • Eunjin Jeong,
  • Hye Lin Kim,
  • Seohee Park,
  • Seojin Jang,
  • Jamin Ku,
  • Hajeong Kim,
  • Haeun Kim,
  • Seo Lyn Choi,
  • Kang Pa Lee,
  • Suji Baek,
  • Jeong-Yoon Yang,
  • Jung Ho Park,
  • Jangok Yeo,
  • Jae Jun Lee,
  • Sei Young Lee,
  • Seok-Hyung Kim,
  • Hong Sook Kim,
  • Chang-Whan Yoon,
  • Sang-Hyuk Lee

摘要

HECT and RCC1-like domain-containing protein 1 (HERC1), a large E3 ubiquitin ligase, has been implicated in neural development and genome stability, but its role in cancer remains unclear. This study identifies HERC1 as a critical regulator of cancer stemness, metastasis, and chemoresistance in head and neck squamous cell carcinoma (HNSCC). CD44⁺ HNSCC organoids with shRNA-mediated HERC1 knockdown were assessed for stemness, EMT, and IL-6/STAT3/HERC1 signaling using molecular assays, CAF co-culture, xenografts, and tissue immunohistochemistry. High HERC1 expression in TCGA-HNSCC datasets was associated with enrichment of stemness signatures. HERC1 knockdown in CD44⁺ cells reduced Sox2, and Slug expression, suppressed EMT, and impaired metastatic potential in Transwell assays and in vivo models. CD44⁺ cells formed organoids in a HERC1-dependent manner. CAF co-culture showed that IL-6 promoted organoid invasiveness through STAT3 activation and HERC1 upregulation. Mechanistic validation revealed that HERC1 modulation altered p-STAT3, p-ERK, CD44, and Slug levels, and STAT3 inhibition reduced HERC1 expression, defining a p-STAT3–HERC1–p-ERK axis. IL-6 neutralization or HERC1 inhibition sensitized organoids to 5-fluorouracil and cisplatin, and combined HERC1 knockdown with 5-FU markedly reduced tumor growth and increased apoptosis. Tissue arrays confirmed elevated HERC1 and pathway markers in advanced HNSCC. These findings define an p-STAT3–HERC1–p-ERK signaling axis that promotes cancer stemness and chemoresistance through CD44+ tumor–stromal crosstalk. Targeting HERC1 may offer a promising strategy to eliminate cancer stem-like cells in HNSCC.