read_status: read
type: paper
title: "The Molecular Motor Myosin 5B and Its Folding Chaperone UNC45A Are Decreased in Colorectal Cancer"
year: 2025
authors:
- "Dooley, Sarah A."
- "Stubler, Rachel"
- "Maity, Priti Parsanna"
- "Múnera, Jorge"
- "Kourtidis, Antonis"
- "Engevik, Melinda A."
- "Engevik, Amy C."
journal: "Cellular and Molecular Gastroenterology and Hepatology"
doi: "10.1016/j.jcmgh.2025.101537"
url: "https://linkinghub.elsevier.com/retrieve/pii/S2352345X25000785"
project:
- EpPathobio
system:
- intestinal_epithelium
- colon_epithelium
- apical_domain
- vesicle_trafficking_pathway
disease:
- colorectal_cancer
genes:
- myo5b
- unc45a
processes:
- promoter_hypermethylation
- epigenetic_gene_silencing
- post_transcriptional_regulation
- protein_folding
- apical_membrane_trafficking
methods:
- dna_methylation_analysis
- demethylation_treatment
- mirna_expression_profiling
- human_colonic_organoids
- cancer_cell_lines
- immunofluorescence_staining
- mass_spectrometry_proteomics
key_findings:
- myo5b_transcriptional_silencing
- unc45a_protein_loss
- mirna_mediated_translation_inhibition
- chaperone_motor_axis_disruption
limitations:
- lack_of_in_vivo_functional_rescue
- incomplete_mechanistic_link_to_tumorigenesis
- mirna_specificity_uncertainty
relevance:
- mechanistic_link_epigenetics_and_trafficking
- tumor_suppressor_axis_in_epithelium
- therapeutic_entry_points_epigenetics_mirna
concepts:
- Epigenetic Control of Trafficking Motors
- Chaperone-Dependent Myosin Function
- miRNA-Mediated Protein Loss in Cancer
tags:
- crc
- epithelial_trafficking
- epigenetics
- mirna
We report that expression of the molecular motor Myosin 5b (MYO5B) and its folding chaperone unc-45 myosin chaperone A (UNC45A) is decreased in colorectal cancer. MYO5B downregulation is driven by promoter hypermethylation, whereas UNC45A protein loss results from posttranscriptional repression by upregulated microRNAs. These findings reveal a previously unrecognized MYO5B–UNC45A regulatory axis disrupted in colorectal cancer and highlights distinct epigenetic and post-transcriptional mechanisms contributing to disease progression.
MYO5B mRNA and protein are consistently reduced in human colorectal cancer samples across stages and subtypes
[[Dooley2025]]
MYO5B downregulation is driven by promoter hypermethylation, not by recurrent coding mutations
Pharmacologic DNA demethylation is sufficient to restore MYO5B expression in CRC cell lines
UNC45A mRNA is unchanged, but UNC45A protein is reduced, indicating post-transcriptional regulation
Multiple miRNAs targeting UNC45A are upregulated in CRC tumors and cell lines
Inhibition of miR-296-3p increases UNC45A protein, demonstrating causal miRNA-mediated repression
Findings define a disrupted MYO5B–UNC45A regulatory axis in colorectal cancer
Integration of TCGA, CPTAC, and public methylation databases
DNA methylation profiling of MYO5B promoter regions
Demethylation assays using 5-aza-2’-deoxycytidine
miRNA target prediction combined with patient and cell line expression data
Human colonic organoids as non-malignant epithelial controls
Immunofluorescence and proteomics to assess protein abundance and localization
miRNA inhibition assays to test causal post-transcriptional regulation
Establishes epigenetic silencing of a vesicle trafficking motor as a cancer-associated mechanism
Separates transcriptional control (MYO5B) from post-transcriptional control (UNC45A)
Highlights how loss of a chaperone can phenocopy loss of its motor client
Frames epithelial polarity and trafficking machinery as tumor suppressive systems
Provides a mechanistic bridge between CRC biology and MVID-associated pathways
Figure 1: MYO5B expression is broadly reduced in CRC and correlates with survival
Figure 2: MYO5B promoter hypermethylation and demethylation rescue
Figure 3: Loss of MYO5B protein and apical localization in CRC tissue
Figure 4: UNC45A protein reduction without mRNA change
Figure 6–7: Upregulation of UNC45A-targeting miRNAs in CRC
Figure 8: miR-296-3p inhibition restores UNC45A protein
No in vivo CRC model directly testing MYO5B or UNC45A restoration
Downstream effects of MYO5B loss on epithelial polarity not functionally dissected
Relative contribution of individual miRNAs to UNC45A repression unresolved
Tumor-suppressive function inferred largely from correlative human data