摘要
Abnormal activation of Wnt/β-catenin-mediated transcription is closely associated with the malignancy of pancreatic cancer.Family with sequence similarity 83 member A(FAM83A)was shown recently to have oncogenic effects in a variety of cancer types,but the biological roles and molecular mechanisms of FAM83A in pancreatic cancer need further investigation.Here,we newly discovered that FAM83A binds directly toβ-catenin and inhibits the assembly of the cytoplasmic destruction complex thus inhibiting the subsequent phosphorylation and degradation.FAM83A is mainly phosphorylated by the SRC non-receptor kinase family member BLK(B-lymphoid tyrosine kinase)at tyrosine 138 residue within the DUF1669 domain that mediates the FAM83A-β-catenin interaction.Moreover,FAM83A tyrosine 138 phosphorylation enhances oncogenic Wnt/β-catenin-mediated transcription through promotingβ-catenin-TCF4 interaction and showed an elevated nucleus translocation,which inhibits the recruitment of histone deacetylases by TCF4.We also showed that FAM83A is a direct downstream target of Wnt/β-catenin signaling and correlates with the levels of Wnt target genes in human clinical pancreatic cancer tissues.Notably,the inhibitory peptides that target the FAM83A-β-catenin interaction significantly suppressed pancreatic cancer growth and metastasis in vitro and in vivo.Our results revealed that blocking the FAM83A cascade signaling defines a therapeutic target in human pancreatic cancer.
基金
We thank the Hubei University of Technology for the research equipment and technical support for this research.This work was supported by the National Natural Science Foundation of China(32070726 and 82273970 to J.F.T.,32270768 to C.F.Z.,31871176 to X.Z.C.,82173043 to W.Z.T.)
Wuhan Science and Technology Project(2019020701011475 to J.F.T.,2022020801020272 to C.F.Z.)
National Natural Science Foundation of Hubei(2020CFA073 to J.F.T.,2022EHB038 to C.F.Z.)
Doctoral Start-up Foundation of Hubei University of Technology(BSQD2020035 to C.F.Z.).
