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

Cell Rep. 2021 Jul 27;36(4):109431. doi: 10.1016/j.celrep.2021.109431.

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.

Keywords: APC mutation; FZD3; HOXC10; KSRP; cis-HOX; colorectal cancer; metastasis; self-renewal; tumor initiating cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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