CircTRIM1 encodes TRIM1-269aa to promote chemoresistance and metastasis of TNBC via enhancing CaM-dependent MARCKS translocation and PI3K/AKT/mTOR activation

Mol Cancer. 2024 May 16;23(1):102. doi: 10.1186/s12943-024-02019-6.

Abstract

Peptides and proteins encoded by noncanonical open reading frames (ORFs) of circRNAs have recently been recognized to play important roles in disease progression, but the biological functions and mechanisms of these peptides and proteins are largely unknown. Here, we identified a potential coding circular RNA, circTRIM1, that was upregulated in doxorubicin-resistant TNBC cells by intersecting transcriptome and translatome RNA-seq data, and its expression was correlated with clinicopathological characteristics and poor prognosis in patients with TNBC. CircTRIM1 possesses a functional IRES element along with an 810 nt ORF that can be translated into a novel endogenously expressed protein termed TRIM1-269aa. Functionally, we demonstrated that TRIM1-269aa, which is involved in the biological functions of circTRIM1, promoted chemoresistance and metastasis in TNBC cells both in vitro and in vivo. In addition, we found that TRIM1-269aa can be packaged into exosomes and transmitted between TNBC cells. Mechanistically, TRIM1-269aa enhanced the interaction between MARCKS and calmodulin, thus promoting the calmodulin-dependent translocation of MARCKS, which further initiated the activation of the PI3K/AKT/mTOR pathway. Overall, circTRIM1, which encodes TRIM1-269aa, promoted TNBC chemoresistance and metastasis by enhancing MARCKS translocation and PI3K/AKT/mTOR activation. Our investigation has yielded novel insights into the roles of protein-coding circRNAs and supported circTRIM1/TRIM1-269aa as a novel promising prognostic and therapeutic target for patients with TNBC.

Keywords: MARCKS; PI3K/AKT/mTOR; TNBC; TRIM1-269aa; circTRIM1.

MeSH terms

  • Animals
  • Calmodulin / metabolism
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm* / genetics
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Microtubule-Associated Proteins* / genetics
  • Microtubule-Associated Proteins* / metabolism
  • Myristoylated Alanine-Rich C Kinase Substrate* / metabolism
  • Neoplasm Metastasis
  • Phosphatidylinositol 3-Kinases* / metabolism
  • Prognosis
  • Proto-Oncogene Proteins c-akt* / metabolism
  • RNA, Circular* / genetics
  • Signal Transduction
  • TOR Serine-Threonine Kinases* / metabolism
  • Transcription Factors* / genetics
  • Transcription Factors* / metabolism
  • Tripartite Motif Proteins / genetics
  • Tripartite Motif Proteins / metabolism
  • Triple Negative Breast Neoplasms* / genetics
  • Triple Negative Breast Neoplasms* / metabolism
  • Triple Negative Breast Neoplasms* / pathology

Substances

  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • MTOR protein, human
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • RNA, Circular
  • TOR Serine-Threonine Kinases
  • Tripartite Motif Proteins
  • MID2 protein, human
  • Microtubule-Associated Proteins
  • Transcription Factors
  • Calmodulin
  • MARCKS protein, human
  • Myristoylated Alanine-Rich C Kinase Substrate