Abstract
Steroid receptor coactivator-1 (SRC-1) is a transcription coactivator playing a pivotal role in mediating a wide range of signaling pathways by interacting with related transcription factors and nuclear receptors. Aberrantly elevated SRC-1 activity is associated with cancer metastasis and progression, and therefore, suppression of SRC-1 is emerging as a promising therapeutic strategy. In this study, we developed a novel SRC-1 degrader for targeted degradation of cellular SRC-1. This molecule consists of a selective ligand for SRC-1 and a bulky hydrophobic group. Since the hydrophobic moiety on the protein surface could mimic a partially denatured hydrophobic region of a protein, SRC-1 could be recognized as an unfolded protein and experience the chaperone-mediated degradation in the cells through the ubiquitin–proteasome system (UPS). Our results demonstrate that a hydrophobic-tagged chimeric molecule is shown to significantly reduce cellular levels of SRC-1 and suppress cancer cell migration and invasion. Together, these results highlight that our SRC-1 degrader represents a novel class of therapeutic candidates for targeting cancer metastasis. Moreover, we believe that the hydrophobic tagging strategy would be widely applicable to develop peptide-based protein degraders with enhanced cellular activity.
Highlights
IntroductionDownregulation of such aberrantly activated proteins has emerged as a legitimate therapeutic strategy [4,5,6]
We demonstrated the utility of Proteolysis-targeting chimeras (PROTACs) based on the N-degron pathway by developing a selective degrader (ND1-YL2) of steroid receptor coactivator-1 (SRC-1) [19]
Immunoblot analysis showed that elevated levels of Hsp70 efficiently increased the cellular activity of YL2-HyT6, leading to Steroid receptor coactivator-1 (SRC-1) degradation even at a concentration that did not affect SRC-1 levels previously (Figure 6d). These results were consistent with a previous study showing enhanced degradation activity toward the androgen receptor after cotreatment with an Hsp90 inhibitor [33]. These results indicate that SRC-1 degradation via hydrophobic tagging strategy can be induced through a chaperone-mediated ubiquitin proteasome system
Summary
Downregulation of such aberrantly activated proteins has emerged as a legitimate therapeutic strategy [4,5,6] To this end, classical genetic techniques such as gene knockouts and small-interfering RNA (siRNA) have been widely used to suppress protein expression at the DNA or mRNA levels [7,8]. Classical genetic techniques such as gene knockouts and small-interfering RNA (siRNA) have been widely used to suppress protein expression at the DNA or mRNA levels [7,8] These conventional methods have been useful, their biological instability and difficulties in delivering such nucleic-acidbased therapeutics have hindered their clinical applications [9,10]. PROTACs have several important advantages compared with conventional biological methods
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