Identification of cis-HOX-HOXC10 axis as a therapeutic target for colorectal tumor-initiating cells without APC mutations.

Colorectal cancer (CRC) is one of the most common cancers worldwide, in which adenomatous polyposis coli (APC) mutations are frequently and uniquely observed. Here we find that cis-HOX (circular RNA stabilizing HOXC10) is robustly expressed in colorectal tumor-initiating cells (TICs). cis-HOX knockout decreases colorectal TIC numbers and impairs the self-renewal, tumorigenesis, and metastatic capacities of TICs, whereas cis-HOX overexpression drives colorectal TIC self-renewal and metastasis. Mechanistically, cis-HOX binds to HOXC10 mRNA to attenuate its decay through blocking the K-homology splicing regulatory protein (KSRP)-binding sequence of HOXC10 3' UTR. HOXC10 is highly expressed in colorectal tumors and TICs and triggers Wnt/β-catenin activation by activating FZD3 expression. HOXC10 inhibitor salinomycin exerts efficient therapeutic effects in APC-wild-type colorectal tumors, but not in tumors with APC nonsense mutations. Therefore, the cis-HOX-HOXC10 pathway drives colorectal tumorigenesis, stemness, and metastasis and serves as a potential therapeutic target for APC-wild-type colorectal tumors.