RING finger protein TOPORS modulates the expression of tumor suppressor SMAR1 in colorectal cancer via the TLR4‐TRIF pathway

Abstract

TOP1‐binding arginine/serine‐rich protein (TOPORS), a really interesting new gene finger protein, has the ability to bind to a palindromic consensus DNA sequence that enables it to function as a potential transcriptional regulator. However, its role in regulating the transcription of cancer‐associated genes is yet to be explored. As Toll‐like receptor 4 (TLR4) agonists are known to regress solid tumors, we observed that lipopolysaccharide (LPS) induces TOPORS via a TLR4‐TIR domain‐containing adapter‐inducing interferon‐β‐dependent pathway, which in turn modulates the transcription of tumor suppressor scaffold/matrix attachment region‐binding protein 1 (SMAR1, also known as BANP). ChIP analysis showed that TOPORS binds on the SMAR1 promoter and its occupancy increases upon LPS treatment. A previous study from our laboratory revealed that SMAR1 acts as a repressor of signal transducer and activator of transcription 3 (STAT3) transcription. Tumor growth, as well as tumor‐associated macrophage polarization, depends on the status of the STAT1:STAT3 ratio. LPS‐induced SMAR1 expression decreases STAT3 expression and also skews the macrophage polarization toward M1 phenotype. In contrast, LPS failed to polarize tumor‐associated macrophages to M1 phenotype in a SMAR1‐silenced condition, which shows the involvement of SMAR1 in dictating the fate of colorectal cancer progression. Identification of the molecular mechanism behind LPS‐mediated tumor regression would be crucial for designing cancer treatment strategies involving bacterial components.

Keywords

• LPS
• SMAR1
• STAT3
• TAM
• TLR4
• TOPORS