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Published on: November 30, 2016
Functional high-throughput screen identifies microRNAs that promote butyrate-induced death in colorectal cancer cells
Saira R Ali1, Karen J Humphreys1, Kaylene J Simpson2,3
1Flinders Health and Medical Research Institute - Cancer Program, Flinders University, Flinders Medical Centre, Bedford Park, SA 5042, Australia.
Abstract:
The gut fermentation product butyrate displays anti-cancer properties in the human proximal colon, including the ability to inhibit proliferation and induce apoptosis in colorectal cancer (CRC) cells. A natural histone deacetylase inhibitor (HDACi), butyrate can alter histone acetylation patterns in CRC cells, and thereby regulate global gene expression, including the non-coding transcriptome and microRNAs (miRNAs). Dysregulated miRNA expression affects CRC development and progression; however, the interplay between miRNA activity and butyrate response remains to be elucidated. A high-throughput functional screen was employed to identify miRNAs that can act as enhancers of the anti-cancer properties of butyrate. Validation studies confirmed that several miRNAs, including miR-125b, miR-181a, miR-593, and miR-1227, enhanced apoptosis, decreased proliferation, and promoted cell-cycle arrest in the presence of butyrate. Pathway analyses of predicted miRNA target genes highlighted their likely involvement in critical cancer-related growth pathways, including WNT and PI3K signaling. Several cancer-associated miRNA targets, including TRIM29, COX2, PIK3R3, CCND1, MET, EEF2K, DVL3, and NUP62 were synergistically regulated by the combination of cognate miRNAs and butyrate. Overall, this study has exposed the potential of miRNAs to act as enhancers of the anti-cancer effects of HDAC inhibition and identifies specific miRNAs that might be exploited for therapeutic benefit.
Insights
Butyrate, a gut microbe product, fights colorectal cancer (CRC) by inhibiting cancer cell growth. Specific microRNAs (miRNAs) can boost butyrate
Area of Science:
- Molecular Biology
- Cancer Research
- Genetics
Background:
- Butyrate, a gut fermentation product, exhibits anti-cancer properties in colorectal cancer (CRC) by inhibiting proliferation and inducing apoptosis.
- Butyrate functions as a natural histone deacetylase inhibitor (HDACi), modulating gene expression, including microRNAs (miRNAs), which are implicated in CRC development.
Purpose of the Study:
- To identify specific microRNAs (miRNAs) that enhance the anti-cancer effects of butyrate in colorectal cancer (CRC).
- To elucidate the interplay between miRNA activity and the cellular response to butyrate treatment.
Main Methods:
- A high-throughput functional screen was utilized to identify miRNAs that potentiate butyrate's anti-cancer activities.
- Validation studies confirmed the effects of identified miRNAs on apoptosis, proliferation, and cell-cycle arrest in CRC cells treated with butyrate.
- Pathway analysis and target gene identification were performed to understand the molecular mechanisms involved.
Main Results:
- Several miRNAs, including miR-125b, miR-181a, miR-593, and miR-1227, were confirmed to enhance butyrate's anti-cancer effects.
- These miRNAs promoted apoptosis, reduced proliferation, and induced cell-cycle arrest in CRC cells when combined with butyrate.
- Synergistic regulation of key cancer-associated genes (e.g., TRIM29, COX2, PIK3R3) by miRNAs and butyrate was observed, involving WNT and PI3K signaling pathways.
Conclusions:
- MicroRNAs can act as enhancers of histone deacetylase inhibition (HDACi) therapy, specifically potentiating the anti-cancer effects of butyrate.
- Specific miRNAs identified in this study hold therapeutic potential for enhancing colorectal cancer (CRC) treatment strategies.
