YTHDF1 promotes the osteolytic bone metastasis of breast cancer via inducing EZH2 and CDH11 translation

Shuoer Wang; Lun Xu; Dongliang Wang; Songjiao Zhao; Kun Li; Fen Ma; Qianlan Yao; Yunkui Zhang; Zhiqiang Wu; Yang Shao; Shaoli Song; Wangjun Yan

doi:10.1016/j.canlet.2024.217047

YTHDF1 promotes the osteolytic bone metastasis of breast cancer via inducing EZH2 and CDH11 translation

Cancer Lett. 2024 Aug 10:597:217047. doi: 10.1016/j.canlet.2024.217047. Epub 2024 Jun 12.

Authors

Shuoer Wang¹, Lun Xu², Dongliang Wang³, Songjiao Zhao⁴, Kun Li², Fen Ma⁵, Qianlan Yao⁶, Yunkui Zhang⁷, Zhiqiang Wu², Yang Shao⁸, Shaoli Song⁹, Wangjun Yan¹⁰

Affiliations

¹ Department of Musculoskeletal Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Nuclear Medicine, Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
² Department of Musculoskeletal Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
³ Department of Nuclear Medicine, Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
⁴ Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁵ Shanghai Key Laboratory of Compound Chinese Medicines, The MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, China; Institute of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China.
⁶ Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
⁷ Department of Anesthesiology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
⁸ Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. Electronic address: [email protected].
⁹ Department of Nuclear Medicine, Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. Electronic address: [email protected].
¹⁰ Department of Musculoskeletal Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. Electronic address: [email protected].

PMID: 38871245
DOI: 10.1016/j.canlet.2024.217047

Abstract

Bone metastasis is common in breast cancer and more effective therapies are required, however, its molecular mechanism is poorly understood. Additionally, the role of the m⁶A reader YTHDF1 in bone metastasis of breast cancer has not been reported. Here, we reveal that the increased expression of YTHDF1 is clinically correlated with breast cancer bone metastases. YTHDF1 promotes migration, invasion, and osteoblast adhesion and induces osteoclast differentiation of cancer cells in vitro and vivo. Mechanically, RNA-seq, MeRIP-seq and RIP-seq analysis, and molecular biology experiments demonstrate that YTHDF1 translationally enhances EZH2 and CDH11 expression by reading m⁶A-enriched sites of their transcripts. Moreover, adeno-associated virus (AAV) was used to deliver shYTHDF1 (shYTHDF1-AAV) in intratibial injection models, eliciting a significant suppressive effect on breast cancer bone metastatic formation and osteolytic destruction. Overall, we uncovered that YTHDF1 promotes osteolytic bone metastases of breast cancer by inducing EZH2 and CDH11 translation.

Keywords: Bone metastatic breast cancer; EZH2; Osteolytic destruction; YTHDF1; m6A.

MeSH terms

Animals
Bone Neoplasms* / genetics
Bone Neoplasms* / metabolism
Bone Neoplasms* / secondary
Breast Neoplasms* / genetics
Breast Neoplasms* / metabolism
Breast Neoplasms* / pathology
Cadherins* / genetics
Cadherins* / metabolism
Cell Differentiation
Cell Line, Tumor
Cell Movement
Enhancer of Zeste Homolog 2 Protein* / genetics
Enhancer of Zeste Homolog 2 Protein* / metabolism
Female
Gene Expression Regulation, Neoplastic
Humans
Mice
Osteoclasts / metabolism
Osteoclasts / pathology
Osteolysis* / genetics
RNA-Binding Proteins* / genetics
RNA-Binding Proteins* / metabolism

Substances

Cadherins
Enhancer of Zeste Homolog 2 Protein
EZH2 protein, human
osteoblast cadherin
RNA-Binding Proteins
YTHDF1 protein, human