USP2 stabilizes POU2F3 and represents a therapeutic vulnerability in POU2F3-positive small cell lung cancer

Small cell lung cancer (SCLC) comprises molecular subtypes, among which POU2F3-driven SCLC (SCLC-P) lacks effective targeted therapies. Because POU2F3 is a lineage-defining transcription factor that remains largely undruggable, defining mechanisms that maintain its protein stability may reveal therapeutic vulnerabilities. Using CRISPR-Cas9 screening and deubiquitinase (DUB) inhibitor profiling, we identified USP2 as a dominant DUB stabilizing POU2F3. Mechanistically, USP2 interacts with and removes K48-linked ubiquitin chains, thereby preventing proteasomal degradation, while K251 and K348 serve as major ubiquitination sites. USP28 also deubiquitinates POU2F3 but exerts relatively weaker effects. Pharmacological inhibition of USP2-associated DUB activity with MS102 increased POU2F3 ubiquitination, accelerated its degradation, and selectively suppressed SCLC-P growth in vitro and in vivo . Re-expression of POU2F3 or a ubiquitination-resistant POU2F3 mutant partially rescued these effects. Together, these findings establish USP2 as a critical proteostatic regulator of POU2F3 and support targeting lineage-specific proteostatic mechanisms as a therapeutic strategy for SCLC-P.