Abstract
Synaptonemal complex protein 3 (SCP3), a member of the Cor1 family, has been implicated in cancer progression, and therapeutic resistance, as well as cancer stem cell (CSC)-like properties. Previously, we demonstrated that SCP3 promotes these aggressive phenotypes via hyperactivation of the AKT signaling pathway; however, the underlying mechanisms responsible for SCP3-induced AKT activation remain to be elucidated. In this study, we demonstrated that the EGF-EGFR axis is the primary route through which SCP3 acts to activate AKT signaling. SCP3 triggers the EGFR-AKT pathway through transcriptional activation of EGF. Notably, neutralization of secreted EGF by its specific monoclonal antibody reversed SCP3-mediated aggressive phenotypes with a concomitant reversal of EGFR-AKT activation. In an effort to elucidate the molecular mechanisms underlying SCP3-induced transcriptional activation of EGF, we identified Jun activation domain-binding protein 1 (JAB1) as a binding partner of SCP3 using a yeast two-hybrid (Y2H) assay system, and we demonstrated that SCP3 induces EGF transcription through physical interaction with JAB1. Thus, our findings establish a firm molecular link among SCP3, EGFR, and AKT by identifying the novel roles of SCP3 in transcriptional regulation. We believe that these findings hold important implications for controlling SCP3high therapeutic-refractory cancer.
Highlights
Introduction published maps and institutional affilSynaptonemal complex protein 3 (SCP3), a member of the Cor1 family, is a structural component of the synaptonemal complex, which mediates synapsis, pairing of homologous chromosomes during meiosis in germ cells [1]; it is mainly expressed in the testis and ovary [2]
We examined whether Jun activation domain-binding protein 1 (JAB1) is required for the epidermal growth factor (EGF)-epidermal growth factor receptor (EGFR) axis mediated by phosphorylation (Figure 5A), which was accompanied by decreased level of EGF protein or mRNA (Figure 5A,B)
Harnessing the immune system to detect and eliminate tumor cells, cancer immunoHarnessing the immune system to detect and eliminate tumor cells, cancer imtherapy has emerged as a promising cancer treatment [20]
Summary
Synaptonemal complex protein 3 (SCP3), a member of the Cor family, is a structural component of the synaptonemal complex, which mediates synapsis, pairing of homologous chromosomes during meiosis in germ cells [1]; it is mainly expressed in the testis and ovary [2]. Previous studies provide evidence that SCP3 is important for tumor progression, metastasis, and immune resistance, as well as cancer stem cell (CSC)-like property [6,7,8]. In this regard, we demonstrated a pathway involved in SCP3-mediated multi-aggressive phenotypes of tumor cells, which is dependent on AKT signaling [6,8]. The underlying mechanisms responsible for SCP3-induced AKT activation remains to be elucidated. iations.
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