Open AccessSALL4 ‐ KHDRBS3 network enhances stemness by modulating CD 44 splicing in basal‐like breast cancer
Author(s) -
Matsumoto Yoshiaki,
Itou Junji,
Sato Fumiaki,
Toi Masakazu
Publication year - 2018
Publication title -
cancer medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 53
ISSN - 2045-7634
DOI - 10.1002/cam4.1296
Subject(s) - gene knockdown , splicing factor , biology , cancer research , rna splicing , cancer stem cell , breast cancer , alternative splicing , cancer , exon , stem cell , microbiology and biotechnology , gene , genetics , rna
Understanding the mechanism by which cancer cells enhance stemness facilitates cancer therapies. Here, we revealed that a stem cell transcription factor, SALL 4, functions to enhance stemness in basal‐like breast cancer cells. We used sh RNA ‐mediated knockdown and gene overexpression systems to analyze gene functions. To evaluate stemness, we performed a sphere formation assay. In SALL 4 knockdown cells, the sphere formation ability was reduced, indicating that SALL 4 enhances stemness. CD 44 is a membrane protein and is known as a stemness factor in cancer. CD 44 splicing variants are involved in cancer stemness. We discovered that SALL 4 modulates CD 44 alternative splicing through the upregulation of KHDRBS 3, a splicing factor for CD 44. We cloned the KHDRBS 3‐regulated CD 44 splicing isoform ( CD 44v), which lacks exons 8 and 9. CD 44v overexpression prevented a reduction in the sphere formation ability by KHDRBS 3 knockdown, indicating that CD 44v is positively involved in cancer stemness. In addition, CD 44v enhanced anoikis resistance under the control of the SALL4 ‐ KHDRBS3 network. Basal‐like breast cancer is an aggressive subtype among breast cancers, and there is no effective therapy so far. Our findings provide molecular targets for basal‐like breast cancer therapy. In the future, this study may contribute to the establishment of drugs targeting cancer stemness.