TET2-mediated epigenetic reprogramming of breast cancer cells impairs lysosome biogenesis

Area of Science:

• Epigenetics
• Cancer Biology
• Molecular Oncology

Background:

• DNA methylation and demethylation regulate gene expression by controlling chromatin structure.
• Cancer cells possess distinct transcriptional programs that drive tumorigenesis.
• The catalytic domain (CD) of TET2 is a key enzyme in DNA demethylation.

Purpose of the Study:

• To investigate the effect of enforced TET2 CD expression on breast cancer cell tumorigenic potential.
• To identify genes regulated by TET2 CD in breast cancer.
• To explore the interplay between TET2 and the MYC oncogenic transcription factor in cancer.

Main Methods:

• Enforced expression of TET2 catalytic domain in breast cancer cells.
• Gene expression profiling (RNA sequencing) to identify differentially expressed genes.
• Analysis of MYC-binding motifs and MYC-regulated genes.
• Assessment of cellular response to autophagy inducers.

Main Results:

• TET2 CD expression decreased the tumorigenic potential of breast cancer cells.
• TET2 CD modulated a unique set of genes compared to decitabine treatment.
• TET2 CD promoted an antiviral state and activated 5-methylcytosine (5mC) turnover at MYC-binding sites.
• TET2 CD down-regulated MYC-repressed genes involved in lysosome biogenesis, inducing a lysosomal storage disease-like state.
• TET2-induced changes sensitized cells to autophagy inducers.

Conclusions:

• Enforced TET2 CD expression represents a potential therapeutic strategy to reduce breast cancer's tumorigenic potential.
• TET2 CD establishes a distinct epigenetic landscape by interacting with MYC, impacting lysosome function and autophagy.
• The cross-talk between TET2 and MYC creates vulnerabilities in cancer cells, such as increased sensitivity to autophagy-based therapies.