The meiosis-specific cohesin component stromal antigen 3 promotes cell migration and chemotherapeutic resistance in colorectal cancer

Chromosome instability is one of the hallmarks of cancer. Stromal antigen (STAG) 3 is a core component of the meiosis-specific cohesin complex, which regulates sister chromatid cohesion. Although aberrantly activated genes encoding the cohesin complex have been identified in cancers, little is known...

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Bibliographic Details
Published in:Cancer letters 2021-01, Vol.497, p.112-122
Main Authors: Sasaki, Masaru, Miyoshi, Norikatsu, Fujino, Shiki, Saso, Kazuhiro, Ogino, Takayuki, Takahashi, Hidekazu, Uemura, Mamoru, Yamamoto, Hirofumi, Matsuda, Chu, Yasui, Masayoshi, Ohue, Masayuki, Mizushima, Tsunekazu, Doki, Yuichiro, Eguchi, Hidetoshi
Format: Article
Language:English
Subjects:
5-Fluorouracil
Aged
Antibodies
Antigens
Antineoplastic Agents - pharmacology
Apoptosis
Biomarkers, Tumor - genetics
Biomarkers, Tumor - metabolism
Cancer
Cell adhesion & migration
Cell Cycle Proteins - genetics
Cell Cycle Proteins - metabolism
Cell migration
Cell Movement
Cell Proliferation
Chemoresistance
Chemotherapy
Cohesin
Cohesin complex
Colorectal cancer
Colorectal carcinoma
Colorectal Neoplasms - drug therapy
Colorectal Neoplasms - metabolism
Colorectal Neoplasms - pathology
Drug Resistance, Neoplasm
DUSP6
ERK
Ewings sarcoma
Extracellular signal-regulated kinase
Female
Gene expression
Gene Expression Regulation, Neoplastic
Humans
Irinotecan
Kinases
Laboratories
Male
Medical prognosis
Medical research
Meiosis
Melanoma
Metastases
Mutation
Neoplasm Metastasis
Neoplasm Recurrence, Local - drug therapy
Neoplasm Recurrence, Local - metabolism
Neoplasm Recurrence, Local - pathology
Organoids
Oxaliplatin
Phosphorylation
Prognosis
Proteins
Snail protein
STAG3
Survival Rate
Transcription
Tumor Cells, Cultured
γH2AX
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Summary:Chromosome instability is one of the hallmarks of cancer. Stromal antigen (STAG) 3 is a core component of the meiosis-specific cohesin complex, which regulates sister chromatid cohesion. Although aberrantly activated genes encoding the cohesin complex have been identified in cancers, little is known about the role of STAG3 in colorectal cancer (CRC). Here, we evaluated the prognostic impact and role of STAG3 in CRC. Analysis of 172 CRC surgical specimens revealed that high STAG3 expression was associated with poor prognosis. STAG3 knockdown inhibited cell migration and increased drug sensitivity to oxaliplatin, 5-fluorouracil, irinotecan hydrochloride hydrate, and BRAF inhibitor in CRC cell lines. The enhanced drug sensitivity was also confirmed in a human organoid established from a CRC specimen. Moreover, suppression of STAG3 increased γH2AX foci. Particularly, in BRAF-mutant CRC cells, STAG3 silencing suppressed the expression of snail family transcriptional repressor 1 and phosphorylation of extracellular signal-regulated kinase via upregulation of dual-specificity phosphatase 6. Our findings suggest that STAG3 is related to poor clinical outcomes and promotes metastasis and chemotherapeutic resistance in CRC. STAG3 may be a novel prognostic marker and potential therapeutic target for CRC. •STAG3 is associated with metastasis and poor prognosis in colorectal cancer (CRC).•STAG3 promotes cell migration and chemotherapeutic resistance in CRC cells.•Suppression of STAG3 increases γH2AX foci in CRC cells.•STAG3 silencing reduces ERK phosphorylation via DUSP6 in BRAF-mutant CRC.•STAG3 silencing enhances chemotherapeutic effects in the patient-derived organoid.
ISSN:0304-3835
1872-7980
DOI:10.1016/j.canlet.2020.10.006