Autophagy: Pro or Anti-tumorigenic? And the role of epigenetics in this debate

Mon, 09/11/2017 - 11:26

By Christina Towers, PhD

Autophagy is an evolutionarily conserved process that cells use to break down damaged cytoplasmic constituents in order to fuel cellular metabolism, particularly in instances of stress. This process has been heavily implicated in a variety of diseases, most noteworthy are neurological disorders and cancer. The role of autophagy in cancer is context dependent and somewhat controversial1. It was originally suggested by Dr. Beth Levine's group that autophagy is tumor suppressive, a claim supported by loss of the core autophagy gene, BECN1, in many tumor types including breast, prostrate, and ovarian2. However, critics of this notion point out the important observation that BECN1 is adjacent to the heavily deleted tumor suppressor gene, BRCA1, suggesting that BECN1 loss could be a passenger deletion rather than a driving one. Thus, leaving open ended the question of the role of autophagy in cancer.

Autophagy Antibody Pack Autophagy Antibody Pack

Immunohistochemistry: Autophagy Antibody Pack [NB910-94159] – (Left) Staining of normal breast tissue. (Right) Staining of breast carcinoma. Stronger immunoreactivity, indicative of greater autophagic activity in normal breast tissue.

Highlighting the context dependent roles of autophagy in cancer, Rao et al. showed that loss of autophagy in a mouse model of kRAS driven non-small cell lung cancer can accelerate tumor development, yet also increase survival in tumor-bearing mice3. Thus, a consensus is starting to emerge from this and many other studies4 indicating a tumor suppressive role for autophagy during early stages of tumor development. In contrast, in established tumors autophagy promotes growth. How can these seemingly divergent roles of autophagy be explained? Investigators believe that early on, autophagy can inhibit tumorigenesis by decreasing chronic tissue damage and inflammation as well as decreasing oncogenic signaling and genomic instability. However, a switch occurs during the development of the disease when autophagy increases cell proliferation, cytokine production, glycolysis and oxidative metabolism thus contributing to tumorigenesis.

In addition to the divergent roles of autophagy in cancer. It is clear that in some cancer types autophagy may be silenced. However, it is unclear how or when cells loose functional autophagy during tumor development. In addition to the aforementioned genetic deletion of BECN1, it has recently been suggested that autophagy may be regulated by heritable modifications of gene expression also known as epigenetics. As an example, the autophagy inducing protocadherin-17 (PCDH17) is heavily methylated and silenced in up to 95% of gastric and colon cancers. Additionally, a variant of the core autophagy gene, LC3, can be inactivated via methylation in esophageal squamous cell carcinoma. And, promoter methylation and inactivation of Sox1 can indirectly inhibit autophagy in non-small cell lung cancer cells 5.

Because the impact of autophagy in tumorigenesis is context dependent, the consequences of these epigenetic regulations have yet to be identified. Nonetheless, these studies indicate that the process of autophagy can now be added to the growing list of important biological pathways implicated in cancer that can be regulated epigenetically.

Learn more about autophagy



  1. Towers, C. G. & Thorburn, A. Therapeutic Targeting of Autophagy. EBioMedicine, doi:10.1016/j.ebiom.2016.10.034 (2016).
  2. Liang, X. H. et al. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 402, 672-676, doi:10.1038/45257 (1999).
  3. Rao, S. et al. A dual role for autophagy in a murine model of lung cancer. Nature communications 5, 3056, doi:10.1038/ncomms4056 (2014).
  4. Levy, J. M. M., Towers, C. G. & Thorburn, A. Targeting autophagy in cancer. Nature reviews. Cancer 17, 528-542, doi:10.1038/nrc.2017.53 (2017).
  5. Sui, X. et al. Epigenetic modifications as regulatory elements of autophagy in cancer. Cancer Lett 360, 106-113, doi:10.1016/j.canlet.2015.02.009 (2015).

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