TRIM69 suppressed the anoikis resistance and metastasis of gastric cancer through ubiquitin‒proteasome-mediated degradation of PRKCD.

The tripartite motif (TRIM) protein family has been investigated in multiple human cancers, including gastric cancer (GC). However, the role of TRIM69 in the anoikis resistance and metastasis of GC cells remains to be elucidated. We identified the differentially expressed genes in anoikis-resistant GC cells using RNA-sequencing analysis. The interaction between TRIM69 and PRKCD was analyzed by coimmunoprecipitation and mass spectrometry. Our results have shown that TRIM69 was significantly downregulated in anoikis-resistant GC cells. TRIM69 overexpression markedly suppressed the anoikis resistance and metastasis of GC cells in vitro and in vivo. TRIM69 knockdown had the opposite effects. Mechanistically, TRIM69 interacted with PRKCD through its B-box domain and catalyzed the K48-linked polyubiquitination of PRKCD. Moreover, TRIM69 inhibited BDNF production in a PRKCD-dependent manner. Importantly, overexpression of PRKCD or BDNF blocked the effects of TRIM69 on the anoikis resistance and metastasis of GC cells. Interestingly, a TRIM69PRKCDBDNF cell subset was positively associated with metastasis in GC patients. TRIM69-mediated suppression of the anoikis resistance and metastasis of GC cells via modulation of the PRKCD/BDNF axis, with potential implications for novel therapeutic approaches for metastatic GC.