E3 ubiquitin ligase WSB1-mediated ubiquitination modification of DIO2 promotes colorectal cancer stemness and metastasis by blocking thyroid hormone signaling

Metastasis represents the major cause of colorectal Cancer (CRC)-related mortality. Here, we sought to examine the mechanism of WD repeat and SOCS box-containing protein 1 (WSB1), an E3 ubiquitin Ligase, in CRC liver metastasis (LM). An orthotopic implantation CRC model was constructed to analyze the differences in gene expression within cecum xenograft tumors (CXTs) and LMs. WSB1 was significantly higher expressed within the LM of nude mice than CXT, whereas type II iodothyronine deiodinase (DIO2) was higher in CXT. WSB1 knockdown hampered LM in CRC with orthotopic tumors, which was reversed by DIO2 knockdown. WSB1 degraded DIO2 by ubiquitination modification. The roles of the WSB1/DIO2/T3/TRβ1 axis in CRC cell proliferation, migration, invasion, and stemness were also probed. Treatment of SW620 cells with knockdown of DIO2 in combination with T3 reversed the malignant progression of CRC in vitro and in vivo caused by knockdown of DIO2, but the intervention of sh-TRβ1 in turn reversed the therapeutic benefit of T3 on malignant progression of CRC. Taken together, our results identify the DIO2 degradation by WSB1 and subsequent impairment of T3/TRβ1 signaling as mechanisms leading to LM in CRC. These findings can inform therapeutic interventions for this event.

Colorectal cancer; DIO2; Liver metastasis; T3/TRβ1 signaling; WSB1.