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Autophagy Upregulates miR-449a Expression to Suppress Progression of Colorectal Cancer

Sheng-Hui Lan^1,2, Shu-Ching Lin³, Wei-Chen Wang³

¹Department of Life Sciences and Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan.

Frontiers in Oncology

|November 5, 2021

Abstract:

Many studies reported that microRNAs (miRNAs) target autophagy-related genes to affect carcinogenesis, however, autophagy-deficiency-related miRNA dysfunction in cancer development remains poorly explored. During autophagic progression, we identified miR-449a as the most up-regulated miRNA. MiR-449a expression was low in the tumor parts of CRC patient specimens and inversely correlated with tumor stage and metastasis with the AUC (area under the curve) of 0.899 and 0.736 as well as poor overall survival rate, indicating that miR-449a has the potential to be a prognostic biomarker. In the same group of CRC specimens, low autophagic activity (low Beclin 1 expression and high p62 accumulation) was detected, which was significantly associated with miR-449a expression. Mechanistic studies disclosed that autophagy upregulates miR-449a expression through degradation of the coactivator p300 protein which acetylates the transcription factor Forkhead Box O1 (FoxO1). Unacetylated FoxO1 translocated to the nucleus and bound to the miR-449a promoter to drive gene expression. Either activation of autophagy by the inducer or overexpression of exogenous miR-449a decreases the expression of target gene LEF-1 and cyclin D1, which lead to decreased proliferation, colony formation, migration, and invasion of CRC cells. Autophagy-miR-449a-tartet genes mediated suppression of tumor formation was further confirmed in the xenograft mouse model. In conclusion, this study reveals a novel mechanism wherein autophagy utilizes miR-449a-LEF1-cyclin D1 axis to suppress CRC tumorigenesis. Our findings open a new avenue toward prognosis and treatment of CRC patients by manipulating autophagy-miR-449a axis.

Insights

Autophagy activates miR-449a, a microRNA that suppresses colorectal cancer (CRC) growth by targeting LEF-1 and cyclin D1. Low miR-449a levels indicate poor prognosis in CRC patients, suggesting a therapeutic target.

Area of Science:

Molecular Biology
Oncology
Cell Biology

Background:

MicroRNAs (miRNAs) regulate gene expression and are implicated in cancer.
Autophagy, a cellular degradation process, plays a complex role in cancer development.
The interplay between autophagy dysfunction and miRNA dysregulation in colorectal cancer (CRC) pathogenesis is not fully understood.

Purpose of the Study:

To investigate the role of autophagy-induced miRNAs in colorectal cancer (CRC) development.
To identify specific miRNAs involved in autophagy-deficiency-related CRC.
To elucidate the mechanistic link between autophagy, miR-449a, and CRC tumorigenesis.

Main Methods:

Analysis of miRNA expression in CRC patient specimens.
Assessment of autophagic activity markers (Beclin 1, p62) in relation to miR-449a levels.
Mechanistic studies involving protein degradation, transcription factor binding, and gene expression analysis.
In vitro cell proliferation, colony formation, migration, and invasion assays.
In vivo xenograft mouse model to evaluate tumor suppression.

Main Results:

miR-449a was identified as the most up-regulated miRNA during autophagic progression.
Low miR-449a expression correlated with advanced CRC stage, metastasis, and poor survival.
Low autophagic activity was significantly associated with reduced miR-449a expression.
Autophagy upregulates miR-449a via p300/FoxO1 pathway, leading to decreased LEF-1 and cyclin D1.
Overexpression of miR-449a or autophagy induction suppressed CRC cell proliferation, migration, and invasion.
Tumor formation was suppressed in a xenograft mouse model by the autophagy-miR-449a axis.

Conclusions:

Autophagy promotes miR-449a expression through a novel p300/FoxO1-dependent mechanism.
The miR-449a/LEF-1/cyclin D1 axis acts as a tumor suppressor in colorectal cancer.
miR-449a serves as a potential prognostic biomarker for CRC.
Targeting the autophagy-miR-449a pathway offers a promising therapeutic strategy for CRC.

Read full analysis

Keywords:

FoxO1 autophagy colorectal cancer miR-449a tumorigenesis

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