Truncating mutation in the autophagy gene UVRAG confers oncogenic properties and chemosensitivity in colorectal cancers

Abstract

Autophagy-related factors are implicated in metabolic adaptation and cancer metastasis. However, the role of autophagy factors in cancer progression and their effect in treatment response remain largely elusive. Recent studies have shown that UVRAG, a key autophagic tumor suppressor, is mutated in common human cancers. Here, we demonstrate that the cancer-related UVRAG frame-shift (FS), which does not result in a null mutation, is expressed as a truncated UVRAGFS in colorectal cancer (CRC) with microsatellite instability (MSI), and promotes tumorigenesis. UVRAGFS abrogates the normal functions of UVRAG, including autophagy, in a dominant-negative manner. Furthermore, expression of UVRAGFS can trigger CRC metastatic spread through Rac1 activation and epithelial-to-mesenchymal transition, independently of autophagy. Interestingly, UVRAGFS expression renders cells more sensitive to standard chemotherapy regimen due to a DNA repair defect. These results identify UVRAG as a new MSI target gene and provide a mechanism for UVRAG participation in CRC pathogenesis and treatment response.

Autophagy-Independent Functions of the Autophagy Machinery

“…In line with this notion, UVRAG is often affected by monoallelic mutations in colorectal and gastric carcinomas with high degrees of genomic instability (so-called microsatellite instable), but these mutations fail to affect autophagic responses (Knaevelsrud et al, 2010). Similarly, a truncated variant of UVRAG expressed by some CRCs has been associated with an autophagy-independent DNA repair defect and consequent increased sensitivity to genotoxic chemotherapy (He et al, 2015). BECN1 appears to share with UVRAG the ability to regulate centrosome functions in an ATG5-independent manner, especially in the context of DNA damage (Park et al, 2014).…”

Energy sensing pathways: Bridging type 2 diabetes and colorectal cancer?

“…Autophagy is important in the switch from normal to malignant colorectal cells. UVRAG is a key autophagy effector and a guardian of chromosomal stability; one recent study discovered that a frame shift mutation leading to shortened form of UVRAG protein, which counteracts most of the tumor-suppressor functions of wild-type UVRAG and promotes tumorigenesis, epithelial-to-mesenchymal transition, and metastasis of colorectal cancer [61, 62]. Other mutations of autophagy related genes (ATG5, ATG2B) were also reported to be associated with colorectal cancer [63, 64].…”

GLTSCR1 Negatively Regulates BRD4‐Dependent Transcription Elongation and Inhibits CRC Metastasis

“…[3,4] MSI not only represents a molecular hallmark of hereditary nonpolyposis Lynch syndrome but also occurs in ≈15-20% of sporadic colorectal cancer (CRC) cases. [3,4] MSI not only represents a molecular hallmark of hereditary nonpolyposis Lynch syndrome but also occurs in ≈15-20% of sporadic colorectal cancer (CRC) cases.…”

“…[6] Accumulating evidence suggests that MSI can predict a more favorable clinical prognosis and an effective response to chemotherapy and immunotherapy. [3,4] Although some microsatellite sites have been elucidated in detail, screening and identification of additional novel functional microsatellite sites are essential for understanding CRC development. Therefore, frameshift mutations usually accumulate in these repeated sequences of target genes in cancers with a high frequency of MSI (MSI-H), resulting in the loss of function of key genes, and could be considered as diagnostic or therapeutic targets.…”