Identification of cis-HOX-HOXC10 axis as a therapeutic target for colorectal tumor-initiating cells without APC mutations
Zhenzhen Chen,
Jiayi Wu,
Benyu Liu,
Guangtan Zhang,
Zhiwei Wang,
Lulu Zhang,
Kaili Wang,
Zusen Fan,
Pingping Zhu
Affiliations
Zhenzhen Chen
School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China; International Joint Laboratory for Protein and Peptide Drugs of Henan Province, Zhengzhou 450001, China; Corresponding author
Jiayi Wu
School of Medicine, Nankai University, 94 Weijin Road, Tianjin 300071, China
Benyu Liu
Research Center of Basic Medicine, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China; CAS Key Laboratory of Infection and Immunity, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
Guangtan Zhang
Department of Gastrointestinal Surgery, Henan Provincial People’s Hospital, People’s Hospital of Henan University, People’s Hospital of Zhengzhou University, No. 7 Weiwu Road, Zhengzhou, Henan Province 450003, China
Zhiwei Wang
School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China
Lulu Zhang
School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China
Kaili Wang
School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China
Zusen Fan
CAS Key Laboratory of Infection and Immunity, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; Corresponding author
Pingping Zhu
School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China; State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou, Henan Province 450052, China; Corresponding author
Summary: 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.
