Fos-related-antigen-1 (Fra-1), a member of the activator protein-1 (AP-1) transcription factor superfamily, has an essential role in cancer progress and metastasis and Fra-1 is considered a therapeutic target in metastatic cancer including metastatic colorectal cancer (mCRC). However, its regulation at protein level has not yet been clearly elucidated. We found that ubiquitin-specific protease 21 (USP21) increases Fra-1 stability by deubiquitinating Fra-1 and enhances the expression of Fra-1 target genes in colon cancer cells. We also showed that USP21 controlled Fra-1-dependent migration and invasion activities. The oncogenic property of USP21 was confirmed by a significant reduction in liver metastasis when USP21-knockdown cancer cells were injected intrasplenically into mice. Consistently, clinicopathological analysis of colorectal cancer patients revealed a correlation of USP21 expression with high-grade carcinoma and life span. These results demonstrate that USP21 enhances Fra-1 stability and AP-1 target gene expression by deubiquitinating Fra-1. Therefore, USP21 is considered an attractive therapeutic target in mCRC with high Fra-1 expression.

CD10 expression was identified as a contributor to cancer progression in several cancers; however, the exact biological significance and mechanism of CD10 expression remains unclear. In addition, CD10 expression in esophageal squamous cell carcinoma (ESCC) has not been studied. We investigated the relationship between CD10 and Twist1. Furthermore, we examined the effect of CD10 on tumorigenicity using in vivo and in vitro systems as well as establishing the clinical significance of CD10 expression in ESCC using large clinical samples. CD10 expression was upregulated by Twist1 and there was a strong correlation between mRNA and protein expression. Twist1 can specifically upregulate CD10 at the transcriptional level via an interaction with the promoter region of CD10 and the proximal E-box CAGGTG in the CD10 promoter was identified as a binding site for Twist1. CD10 is frequently expressed in ESCC cell lines and silencing CD10 suppresses migration/invasion and anchorage-independent tumor growth of ESCC cells. Knockdown of CD10 inhibits the growth of ESCC xenograft in nude mice, suggesting that CD10 plays a role in enhancing the tumorigenesis of ESCC. From among 153 ESCC samples, 46 (30.0%) showed varying degrees of CD10 expression in cancer cells. In addition, stromal fibroblasts also showed varying amounts of CD10 expression in 92 (60.9%) tumor samples. CD10 overexpression in cancer cells as well as in stromal fibroblasts was an independent poor prognostic factor in both overall survival and disease-free survival. CD10 could be a promising target for the treatment of ESCC.

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.