TRIM21-mediated ubiquitination of PARP1 suppresses small cell lung cancer progression through the PI3K/AKT/STAT5A axis

Abstract Abnormal accumulation of Poly(ADP-ribose) polymerase 1 (PARP1) is implicated in the progression of several cancers. However, the mechanisms responsible for PARP1 protein stabilization remain incompletely understood. In this study, we identify E3 ubiquitin ligase tripartite motif-containing 21 (TRIM21) as a novel PARP1-binding partner. PARP1 directly interacts with TRIM21 via its HD domain, while the PRY-SPRY domain of TRIM21 is essential for this interaction. Consequently, TRIM21 facilitates the polyubiquitination of PARP1 at the K654 residue, promoting its degradation under physiological conditions. Functionally, we show that TRIM21 is significantly downregulated in small cell lung cancer (SCLC), and its tumor-suppressive potential appears partly mediated by its interaction with PARP1 and the subsequent degradation of PARP1, which supports DNA damage repair and maintains genomic integrity. Additionally, we reveal that the PI3K/AKT pathway suppresses TRIM21 expression through transcription factor STAT5A, which impedes the ubiquitination and degradation of PARP1. Notably, combining the PI3K/AKT inhibitor PKI-587 with the PARP inhibitor (PARPi) BMN673 yields enhanced anti-tumor effects in both in vitro and in vivo models of SCLC. Collectively, our findings establish the “PI3K/AKT-STAT5A-TRIM21-PARP1” signaling axis as a critical pathway in SCLC tumorigenesis. Dual inhibition of this axis with PI3K/AKT inhibitors and PARPi offers promising therapeutic potential for SCLC treatment.