TY - JOUR
T1 - YTHDF3 promotes breast cancer osteolytic bone metastasis by enhancing the translation of ZEB1 and SMAD5
AU - Xu, Lun
AU - Yu, Qian
AU - Peihang, Xu
AU - Li, Kun
AU - Wang, Bingnan
AU - Shao, Yang
AU - cheng, Mo
AU - Huang, Wending
AU - Yao, Qianlan
AU - Feng, Xu
AU - Song, Shaoli
AU - Wang, Shuoer
AU - Yan, Wangjun
N1 - Publisher Copyright:
© The Author(s) 2025.
PY - 2025/12
Y1 - 2025/12
N2 - Bone metastsis in advanced breast cancer patients are usually osteolytic. A better understanding of the mechanisms in osteolytic metastasis is critical for the development of new therapies. YTH domain-containing family protein 3 (YTHDF3) has been reported to function as an N6-methyladenosine (m6A)-modified mRNA regulator. In this study, we found YTDHF3 expression was associated with clinical characteristics of breast cancer patients. YTHDF3 expression influenced the migration and invasion capacity of breast cancer cells in vitro and in vivo, and low expression of YTHDF3 suppressed cancer cell-induced osteoclast differentiation and osteolytic bone destruction. Moreover, we found YTHDF3 enhanced the translation of zinc finger E-box-binding protein 1 (ZEB1) and SMAD family member 5 (SMAD5) by reading the m6A modification sites in their mRNAs and further promoted the epithelial-mesenchymal transition (EMT) of breast cancer cells. Enhanced expression of ZEB1 promoted the transcription of bone morphogenetic protein inhibitors such as NOG, FST and CCN2, which boosts osteolytic metastasis. Furthermore, we newly found Wnt family member 5B (WNT5B) expression was regulated by ZEB1, also involved in osteolytic process. In conclusion, YTHDF3 plays an important role in osteolytic metastasis and it may serve as a potential prognostic biomarker and therapeutic target for breast cancer bone metastasis.
AB - Bone metastsis in advanced breast cancer patients are usually osteolytic. A better understanding of the mechanisms in osteolytic metastasis is critical for the development of new therapies. YTH domain-containing family protein 3 (YTHDF3) has been reported to function as an N6-methyladenosine (m6A)-modified mRNA regulator. In this study, we found YTDHF3 expression was associated with clinical characteristics of breast cancer patients. YTHDF3 expression influenced the migration and invasion capacity of breast cancer cells in vitro and in vivo, and low expression of YTHDF3 suppressed cancer cell-induced osteoclast differentiation and osteolytic bone destruction. Moreover, we found YTHDF3 enhanced the translation of zinc finger E-box-binding protein 1 (ZEB1) and SMAD family member 5 (SMAD5) by reading the m6A modification sites in their mRNAs and further promoted the epithelial-mesenchymal transition (EMT) of breast cancer cells. Enhanced expression of ZEB1 promoted the transcription of bone morphogenetic protein inhibitors such as NOG, FST and CCN2, which boosts osteolytic metastasis. Furthermore, we newly found Wnt family member 5B (WNT5B) expression was regulated by ZEB1, also involved in osteolytic process. In conclusion, YTHDF3 plays an important role in osteolytic metastasis and it may serve as a potential prognostic biomarker and therapeutic target for breast cancer bone metastasis.
UR - https://www.scopus.com/pages/publications/105022083444
U2 - 10.1038/s41389-025-00583-0
DO - 10.1038/s41389-025-00583-0
M3 - 文章
AN - SCOPUS:105022083444
SN - 2157-9024
VL - 14
JO - Oncogenesis
JF - Oncogenesis
IS - 1
M1 - 41
ER -
