DCTN2 inhibited cellular senescence through targeting TRIM21 mediated MST2 ubiquitination and activation in hepatocellular carcinoma

Rationale: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality, and inducing cellular senescence presents a promising therapeutic approach.However, the mechanisms underlying senescence in HCC pathogenesis remain unclear.This study investigated key genes involved in liver cancer senescence.Methods: Bioinformatic analyses of HCC datasets identified senescence-related genes, highlighting dynactin subunit 2 (DCTN2).We investigated DCTN2's biological function and regulatory mechanism, analyzed its association with patient prognosis, evaluated the synergistic effects of vilazodone and sorafenib in vitro and in vivo, and examined tumor protein p53 (TP53) mutation-mediated regulation of DCTN2.Results: DCTN2 was identified as a novel HCC senescence-associated gene, whose expression was transcriptionally upregulated by TP53 mutation.DCTN2 knockdown induced cellular senescence, thereby inhibiting HCC cell proliferation, migration, invasion and angiogenesis, whereas its overexpression exerted an opposite oncogenic effect.DCTN2 repressed cellular senescence via interaction with TRIM21, which decreased MST2 K63-linked polyubiquitination and ultimately attenuated the Hippo signaling pathway; DCTN2 overexpression correlated with poor HCC prognosis.Moreover, targeting TRIM21 with vilazodone and sorafenib synergistically induced HCC cellular senescence in vitro and in vivo.Conclusions: Our findings revealed that DCTN2 suppresses cellular senescence by inhibiting the Hippo signaling pathway in HCC.Targeting the DCTN2/TRIM21/MST2 axis, along with TP53 mutation regulation, offers new therapeutic insights for HCC treatment.