CANCER SCIENCE
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2024
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IF 4.5
Luhaoran Sun,Zeyu Li,Peng Shu,Min Lu
High expression of truncated O-glycans Tn antigen predicts adverse clinical outcome in patients with clear cell renal cell carcinoma (ccRCC). To understand the biosynthetic underpinnings of Tn antigen changes in ccRCC, we focused on N-acetylgalactosaminyltransferases (GALNTs, also known as GalNAcTs) known to be involved in Tn antigen synthesis. Data from GSE15641 profile and local cohort showed that GALNT6 was significantly upregulated in ccRCC tissues. The current study aimed to determine the role of GALNT6 in ccRCC, and whether GALNT6-mediated O-glycosylation aggravates malignant behaviors. Gain- and loss-of-function experiments showed that overexpression of GALNT6 accelerated ccRCC cell proliferation, migration, and invasion, as well as promoted ccRCC-derived xenograft tumor growth and lung metastasis. In line with this, silencing of GALNT6 yielded the opposite results. Mechanically, high expression of GALNT6 led to the accumulation of Tn antigen in ccRCC cells. By undertaking immunoprecipitation coupled with liquid chromatography/mass spectrometry, vicia villosa agglutinin blot, and site-directed mutagenesis assays, we found that O-glycosylation of prohibitin 2 (PHB2) at Ser161 was required for the GALNT6-induced ccRCC cell proliferation, migration, and invasion. Additionally, we identified lens epithelium-derived growth factor (LEDGF) as a key regulator of GALNT6 transcriptional induction in ccRCC growth and an upstream contributor to ccRCC aggressive behavior. Collectively, our findings indicate that GALNT6-mediated abnormal O-glycosylation promotes ccRCC progression, which provides a potential therapeutic target in ccRCC development.
研究领域:
癌症生物学
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分子生物学
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细胞生物学
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肿瘤学
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产品关联
DOI
PubMed
高影响因子
Cancer Cell International
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2024
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IF 5.3
Boya Deng,Siyang Zhang,Yingying Zhou,Ting Sun,Ying Zhu,Jing Fei,Ailin Li,Yuan Miao
Coiled-coil domain containing 88C (CCDC88C) is a component of non-canonical Wnt signaling, and its dysregulation causes colorectal cancer metastasis. Dysregulated expression of CCDC88C was observed in lymph node metastatic tumor tissues of breast cancer. However, the role of CCDC88C in breast cancer metastasis remains unclear. To address this, the stable BT549 and SKBR3 cell lines with CCDC88C overexpression or knockdown were developed. Loss/gain-of-function experiments suggested that CCDC88C drove breast cancer cell motility in vitro and lung and liver metastasis in vivo. We found that CCDC88C led to c-JUN-induced transcription activation. Overlapping genes were identified from the genes modulated by CCDC88C and c-JUN. CEMIP , one of these overlapping genes, has been confirmed to confer breast cancer metastasis. We found that CCDC88C regulated CEMIP mRNA levels via c-JUN and it exerted pro-metastatic capabilities in a CEMIP-dependent manner. Moreover, we identified the CCDC88C as a substrate of polypeptide N-acetylgalactosaminyltransferase 6 (GALNT6). GALNT6 was positively correlated with CCDC88C protein abundance in the normal breast and breast cancer tissues, indicating that GALNT6 might be associated with expression patterns of CCDC88C in breast cancer. Our data demonstrated that GALNT6 maintained CCDC88C stability by promoting its O-linked glycosylation, and the modification was critical for the pro-metastatic potential of CCDC88C. CCDC88C also could mediate the pro-metastatic potential of GALNT6 in breast cancer. Collectively, our findings uncover that CCDC88C may increase the risk of breast cancer metastasis and elucidate the underlying molecular mechanisms. Supplementary Information The online version contains supplementary material available at 10.1186/s12935-024-03413-2.
研究领域:
癌症生物学
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分子生物学
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细胞生物学
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生物化学
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产品关联
DOI
PubMed
高影响因子
CELLULAR SIGNALLING
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2025
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IF 3.7
Suli Chong,Yang Liu,Ziming Bian,Dongxue Hu,Shiqun Guo,Chenfei Dong,Jiayue Zeng,Sairong Fan,Xiaoming Chen
Despite significant advancements in immunotherapy for cancer treatment, its effectiveness in pancreatic ductal adenocarcinoma (PDAC) remains disappointing, which is greatly due to the unique immunosuppressive microenvironment of PDAC. Here, we focus on the involvement of GALNT6 in immune evasion mechanisms in PDAC. Our results reveal a negative relationship between GALNT6 expression and immune cell infiltration in PDAC. Knockdown of GALNT6 enhances PDAC cells sensitivity to cytotoxic T cells and macrophages. Mechanistically, GALNT6-mediated glycosylation blocks the translocation of STING (stimulator of interferon genes) and accelerates its degradation in a cGAS-independent manner, leading to reduced levels of type I interferon (IFN-β) and CCL5 and CXCL10, thus promoting PDAC immune evasion by inhibiting cytotoxic CD8 + T cell and macrophage infiltration. Furthermore, GALNT6 stabilizes PD-L1 by blocking its ubiquitin-proteasome degradation, thereby promoting tumor immune evasion. Notably, the combination of an O-glycosylation inhibitor with PD-1/PD-L1 inhibitors synergistically enhances the anti-cancer immune response. In summary, these findings highlight GALNT6 as a critical player in immune evasion, and targeting GALNT6 could serve as a valuable approach to boost anti-tumor immunity in PDAC patients.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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