Ubiquitin ligase TRIM63 regulates HOXA10 expression to mediate fatty acid β-oxidation and suppress lung adenocarcinoma metastasis

While it is clear that HOXA10 plays a role in the growth and metastasis of lung adenocarcinoma (LUAD), the details of its regulation are still largely a mystery. Our research sheds new light on this issue by revealing increased HOXA10 protein levels within LUAD tumors. Assays involving colony formation, wound healing, Transwell migration, and western blot (WB) demonstrated that LUAD cell proliferation, migration, and invasion were inhibited by HOXA10 knockdown, as were the expressions of proteins associated with epithelial-mesenchymal transition and metastasis. Overexpression of HOXA10 had the opposite impact. Nude mouse models of subcutaneous allografts and pulmonary metastasis showed that LUAD growth and metastasis were strongly curtailed by HOXA10 knockdown. Gene set enrichment analysis also highlighted a relationship between HOXA10 and the fatty acid β-oxidation (FAO) pathway. Analyses using BODIPY 493/503 staining and WB techniques demonstrated that knocking down HOXA10 in LUAD cells increased lipid accumulation and reduced FAO and key gene expression. The suppressive effects of HOXA10 knockdown on LUAD cell migration were neutralized by the addition of recombinant human Carnitine Palmitoyltransferase 1B (CPT1B) (rhCPT1B) protein. Our research also revealed an interaction between HOXA10 and tripartite motif containing 63 (TRIM63), where TRIM63 overexpression led to HOXA10 degradation through ubiquitination. Overexpression of TRIM63 decreased LUAD cell migration, but this effect was counteracted by HOXA10 overexpression. In summary, the discovery that TRIM63 orchestrates HOXA10 degradation to regulate FAO and curb LUAD matastasis suggests that interventions along the TRIM63-HOXA10 axis could be a fruitful approach to LUAD therapy.