Autophagy maintains homeostasis and balance of microRNAs to prevent cancer occurrence

Autophagy maintains homeostasis and balance of microRNAs to prevent cancer occurrence

     Autophagy plays an essential role in maintaining cellular homeostasis to protect cells from stress-caused damage through the degradation machinery. Dysfunction of autophagy contributes to various human diseases including neurodegenerative disorders and cancers. MicroRNAs (miRNAs) are 20~23 nucleotide non-coding RNAs. Most of them regulate gene expression either by degrading target RNAs or by blocking translation through complementary binding with the 3′ untranslated region (3′ UTR) of the target RNA. MiRNAs participate in diverse biological functions for cell differentiation, proliferation, longevity, and diseases including cancers. Increasing evidence indicate that autophagy plays an anti-tumor role in the early stage of tumorigenesis. Conversely, it shifts to pro-tumor role in late stages of tumorigenesis. Similarly, miRNAs act either as a tumor suppressor or as an oncogene based on the genes they target in different cancers. Since both autophagy and miRNAs participate in tumorigenesis, their relationship warrants extensive exploration. Notably, many studies investigated how miRNAs regulate autophagy-related genes to affect cancer development. In contrast, very few studies explore how autophagy regulates miRNAs to affect tumorigenesis. Therefore, we developed a cell-line system to screen autophagy regulated miRNAs which are involved in tumor formation. We identified one autophagy negatively regulated miRNA (miRNA-224) and one positively regulated miRNA (miR-449a) using miRNA microarray. For the miRNA negatively regulated by autophagy, miR-224 is preferentially delivered to the autophagosome for degradation, which results in upregulation of Smad4 to suppress liver cancer formation (HCC) (Hepatology, 2014).

    For the miRNA positively regulated by autophagy, we revealed that in colorectal cancer (CRC) tumors, autophagy selectively degrades the coactivator p300 histone acetyltransferase, which is responsible for acetylation of Forkhead box protein O1 (FOXO1), as well as prevents its migration from the cytoplasm to the nucleus. We confirmed that FoxO1, as a transcription factor, is responsible for the expression of miR-449a. Activation of autophagy promotes nuclear translocation of FoxO1 followed by binding with the miR-449a promoter to trigger miR-449a transcription. Autophagy positively regulates miRNA expression through degradation of p300, which results in nuclear translocation of the un-acetylated FoxO1 to transcribe miR-449a gene. During the development of CRC, autophagic activity was decreased. This phenomenon results in the increase of p300 level and FoxO1 acetylation. Finally, the transcriptional level of miR-449a is suppressed, which results in overexpression of LEF-1 and cyclinD1 (target genes of miR-449a) followed by cancer development (Frontiers in Oncology, 2022). Low autophagic activity, high miR-224 as well as low expression of miR-449a in HCC and CRC have been reported. Accordingly, we confirmed the association between autophagic activity and two differentially expressed miRNAs in HCC and CRC cell lines. These findings imply that autophagy machinery simultaneously balances the degradation and synthesis of miR-224 and miR-449a, respectively, to maintain cellular homeostasis during adaptation to tumorigenic stresses. Dysfunction of regulation of either one or both miRNAs trigger tumors development. In conclusion, our findings open a new avenue toward manipulating autophagy degradation system to control the balance of miRNAs and maintain the normal functions of the cell.

Graphical Abstract

Application and Highlights:

1. Revealing that in CRC development, low autophagic activity results in low expression of miR-449a accompanied by overexpression of two target genes LEF-1 and cyclinD1 which trigger tumor formation and increased mobility.

2. Demonstrating how autophagy balances the degradation of miR-224 and the synthesis of miR-449a to avoid the occurrence of liver and colorectal cancer.

Research Team Members: Hsiao-Sheng Liu, Pei-Wn Lin, Man-Lin Chu, Yu-Wen, Liu, Sheng-Hui Lan, and Shan-Ying Wu

Representative Department:

◆Dr. Hsiao-Sheng Liu:

1. Center for Cancer Research, Graduate Institute of Clinical   Medicine;

2. Master of Science Program in Tropical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung,

Taiwan

◆Dr. Pei-Wen Lin:

1. Center for Cancer Research, Graduate Institute of Clinical   Medicine;

2. Master of Science Program in Tropical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung,

Taiwan

◆Man-Lin Chu:

Master of Science Program in Tropical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung,

Taiwan

◆Yu-Wen Liu:

1. Center for Cancer Research, Graduate Institute of Clinical   Medicine;

2. Master of Science Program in Tropical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung,

Taiwan

◆Dr. Sheng-Hui Lan:

Department of Life Science and Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei,

Taiwan

◆Dr. Shan-Ying Wu:

Department of Microbiology and Immunology, College of Medicine, Taipei Medical University, Taipei, Taiwan

Introduction of Research Team: 

    The mission of this team is to establish an autophagy analysis platform at the Center of Cancer Research, KMU to study the interrelationship and possible mechanisms of action between various cancers and viral infections and autophagy. The ultimate goal is to develop novel strategies to maintain the homeostasis of cell physiological functions and the balance of miRNAs to alleviate disease symptoms through manipulating autophagy activity.

Contact Email: hsliu@kmu.edu.tw