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Systematic characterization of cancer-associated SPOP mutants reveals novel and reprogrammable degradative activities

ABSTRACT: Speckle-type POZ protein (SPOP) functions as the substrate adaptor of the Cullin3-RING ligase (CRL3) complex and is recurrently mutated in multiple cancer types. Among these, F102C and F133L are frequent prostate cancer mutations within the substrate-binding domain, yet their biochemical consequences remain incompletely understood. Using quantitative proteomics, we show that SPOP-F133L, unlike SPOP-F102C, retains degradative activity toward the nuclear basket proteins NUP153 and TPR, indicating substrate-dependent loss-of-function. Moreover, SPOP-F133L induces partial down-regulation of p53 through a CRL-dependent, post-translational mechanism, revealing a potential neo-substrate relationship. Finally, we demonstrate that both SPOP-F102C and SPOP-F133L support targeted protein degradation (TPD) in an engineered cellular system. These findings define the degradative capacities of SPOP mutants and highlight opportunities to repurpose these variants as mutant-selective E3 ligases for therapeutic applications.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Kidney

DISEASE(S): Prostate Adenocarcinoma

SUBMITTER: Xiaoyu Zhang

LAB HEAD: Xiaoyu Zhang

PROVIDER: PXD071054 | Pride | 2025-12-17

REPOSITORIES: Pride

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			Action	DRS
	HEK293T_SPOP_Halo_JQ1_WP_RTS_16plex_01.raw	Raw
	HEK293T_SPOP_Halo_JQ1_WP_RTS_16plex_02.raw	Raw
	HEK293T_SPOP_Halo_JQ1_WP_RTS_16plex_03.raw	Raw
	HEK293T_SPOP_Halo_JQ1_WP_RTS_16plex_04.raw	Raw
	HEK293T_SPOP_Halo_JQ1_WP_RTS_16plex_05.raw	Raw

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Effects of SPOP on gene expression in prostate cancer

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