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

Life Sci Alliance. 2022 Mar 29;5(7):e202101283. doi: 10.26508/lsa.202101283. Print 2022 Jul.


Methylation and demethylation of cytosines in DNA are believed to act as keystones of cell-specific gene expression by controlling the chromatin structure and accessibility to transcription factors. Cancer cells have their own transcriptional programs, and we sought to alter such a cancer-specific program by enforcing expression of the catalytic domain (CD) of the methylcytosine dioxygenase TET2 in breast cancer cells. The TET2 CD decreased the tumorigenic potential of cancer cells through both activation and repression of a repertoire of genes that, interestingly, differed in part from the one observed upon treatment with the hypomethylating agent decitabine. In addition to promoting the establishment of an antiviral state, TET2 activated 5mC turnover at thousands of MYC-binding motifs and down-regulated a panel of known MYC-repressed genes involved in lysosome biogenesis and function. Thus, an extensive cross-talk between TET2 and the oncogenic transcription factor MYC establishes a lysosomal storage disease-like state that contributes to an exacerbated sensitivity to autophagy inducers.

MeSH terms

  • Breast Neoplasms* / genetics
  • Breast Neoplasms* / metabolism
  • DNA Methylation
  • DNA-Binding Proteins* / genetics
  • Dioxygenases* / genetics
  • Epigenesis, Genetic*
  • Female
  • Humans
  • Lysosomes / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-myc


  • DNA-Binding Proteins
  • MYC protein, human
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-myc
  • Dioxygenases
  • TET2 protein, human