Abstract
The cellular stress response autophagy has been implicated in various diseases including neuro-degeneration and cancer. The role of autophagy in cancer is not clearly understood and both tumour promoting and tumour suppressive effects of autophagy have been reported, which complicates the design of therapeutic strategies based on targeting the autophagy pathway. Here, we have systematically analyzed gene expression data for 47 autophagy genes for deletions, amplifications and mutations in various cancers. We found that several cancer types have frequent autophagy gene amplifications, whereas deletions are more frequent in prostate adenocarcinomas. Other cancer types such as glioblastoma and thyroid carcinoma show very few alterations in any of the 47 autophagy genes. Overall, individual autophagy core genes are altered at low frequency in cancer, suggesting that cancer cells require functional autophagy. Some autophagy genes show frequent single base mutations, such as members of the ULK family of protein kinases. Furthermore, we found hotspot mutations in the arginine-rich stretch in MAP1LC3A resulting in reduced cleavage of MAP1LC3A by ATG4B both in vitro and in vivo, suggesting a functional implication of this gene mutation in cancer development.
Highlights
Autophagy is a highly conserved process that serves two main functions in the cell: to provide energy under conditions of limited nutrient availability and to remove damaged organelles such as misfolded protein aggregates or non-functional mitochondria from the cell
Our results reflect a static snapshot of autophagy gene expression in various cancers and do not take into account the developmental or dynamic nature of individual cancer types
We have explored two areas: firstly, we analysed autophagy gene alterations and mutations in various cancer types as extracted from publicly available data sets, and secondly, we interrogated whether individual autophagy gene products are significantly altered in various cancers
Summary
Autophagy is a highly conserved process that serves two main functions in the cell: to provide energy under conditions of limited nutrient availability and to remove damaged organelles such as misfolded protein aggregates or non-functional mitochondria from the cell. In addition to BECN1, frameshift mutations in core autophagy genes ATG2B, ATG5, ATG9B and ATG12 in colorectal cancers have been reported, providing additional evidence for a tumour suppressive role [9]. We observed reduced LC3A processing and LC3Apositive puncta formation as a consequence of the R70H mutation, suggesting a functional role.
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