MassIVE MSV000093611

Partial Public PXD047661

Proteostasis perturbation of N-Myc by HSP70 inhibition improves treatment in neuroendocrine prostate cancer

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Description

N-Myc is a key driver of neuroendocrine tumors, such as neuroblastoma and neuroendocrine prostate cancer. However, N-Myc is considered undruggable because it lacks clear binding sites for small molecules. One potential way to circumvent this challenge is to identify and target the protein homeostasis proteostasis systems that maintain N-Myc levels. Here we developed a novel spontaneously indefinite prostate cancer cell line UCDCaP and its paired castration-resistant line UCDCaP-CR, which exhibits neural lineage plasticity and high levels of N-Myc protein expression. Through rapid immunoprecipitation mass spectrometry assay, we revealed that heat shock protein 70, HSP70 is a top partner for N-Myc. HSP70 is known to function in protein folding and it also coordinates with the E3 ubiquitin ligase, STIP1 homology and U-box containing protein 1, STUB1, to regulate oncoprotein degradation. We find that HSP70 binds a conserved SELILKR motif and prevents the access of STUB1 on N-Myc possibly through steric hindrance. When HSP70 dwell time on N-Myc is increased by the conformational change of HSP70, STUB1 is in close proximity with N-Myc and becomes functional to promote N-Myc ubiquitination on the K416 and K419 sites of the bHLH-LZ domain and form the poly ubiquitination chains linked by the K11 and K63 sites. [doi:10.25345/C5NS0M83T] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: Prostate cancer, Neuroendocrine, Proteostasis, N-Myc, HSP70, STUB1, Ubiquitination, Therapy

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Principal Investigators:
(in alphabetical order) 		Chengfei Liu, University Of California, Davis, USA
Submitting User: gabrig
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