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

Abstract

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.

• Authors: Zhenzhen Chen, Jiayi Wu, Benyu Liu, Guangtan Zhang, Zhiwei Wang, Lulu Zhang, Kaili Wang, Zusen Fan, Pingping Zhu
• Journal: Cell reports (Cell Rep) Vol. 36 Issue 4 Pg. 109431 (07 27 2021) ISSN: 2211-1247 [Electronic] United States
• PMID: 34320348 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• FZD3 protein, human
• Frizzled Receptors
• HOXC10 protein, human
• Homeodomain Proteins
• Pyrans
• RNA, Circular
• RNA, Messenger
• RNA-Binding Proteins
• salinomycin

Topics

• Adenomatous Polyposis Coli (genetics)
• Aged
• Aged, 80 and over
• Animals
• Carcinogenesis (genetics, pathology)
• Cell Line, Tumor
• Cell Self Renewal
• Colorectal Neoplasms (drug therapy, genetics)
• Female
• Frizzled Receptors (metabolism)
• Gene Expression Regulation, Neoplastic
• Homeodomain Proteins (genetics, metabolism)
• Humans
• Male
• Mice, Knockout
• Molecular Targeted Therapy
• Mutation (ethics)
• Neoplastic Stem Cells (metabolism, pathology)
• Pyrans (pharmacology)
• RNA Stability (genetics)
• RNA, Circular (genetics, metabolism)
• RNA, Messenger (genetics, metabolism)
• RNA-Binding Proteins (metabolism)
• Wnt Signaling Pathway
• Mice