FAVL elevation in human tumors disrupts Fanconi anemia pathway signaling and promotes genomic instability and tumor growth
Jun Zhang, Deping Zhao, Hwan Ki Park, Hong Wang, Roy B. Dyer, Wanguo Liu, George G. Klee, Mark A. McNiven, Donald J. Tindall, Julian R. Molina, Peiwen Fei
Jun Zhang, Deping Zhao, Hwan Ki Park, Hong Wang, Roy B. Dyer, Wanguo Liu, George G. Klee, Mark A. McNiven, Donald J. Tindall, Julian R. Molina, Peiwen Fei
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Research Article Oncology

FAVL elevation in human tumors disrupts Fanconi anemia pathway signaling and promotes genomic instability and tumor growth

Abstract

Fanconi anemia (FA) is a rare human genetic disease caused by mutations in any one of 13 known genes that encode proteins functioning in one common signaling pathway, the FA pathway, or in unknown genes. One characteristic of FA is an extremely high incidence of cancer, indicating the importance of the FA pathway in tumor suppression. However, the role of this pathway in the development and progression of human cancers in individuals who do not have FA has not been clearly determined. Here, we report that elevated expression of what we believe to be a novel splice variant of FA complementation group L (FANCL), which we identified and named FAVL, can impair the FA pathway in non-FA human tumor cells and act as a tumor promoting factor. FAVL expression was elevated in half of the human carcinoma cell lines and carcinoma tissue samples tested. Expression of FAVL resulted in decreased FANCL expression by sequestering FANCL to the cytoplasm and enhancing its degradation. Importantly, this impairment of the FA pathway by FAVL elevation provided human cancer cells with a growth advantage, caused chromosomal instability in vitro, and promoted tumor development in a xenograft mouse model. These data indicate that FAVL impairment of the FA pathway likely contributes to the development of non-FA human cancers and therefore add a challenging layer of complexity to the pathogenesis of human cancer. We further believe that these data will prove useful for developing additional tools for fighting human cancer.

Authors

Jun Zhang, Deping Zhao, Hwan Ki Park, Hong Wang, Roy B. Dyer, Wanguo Liu, George G. Klee, Mark A. McNiven, Donald J. Tindall, Julian R. Molina, Peiwen Fei

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Figure 6

Overexpression of FAVL leads to chromosomal instability.

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Overexpression of FAVL leads to chromosomal instability. (A) Genomic DNA...
(A) Genomic DNA was isolated from control U2OS cells and U2OS cells with elevated levels of FAVL, respectively. Both DNA samples were sent to MOgene LC for array CGH analysis through the dye swap approach. Chromosomal alterations occurred on nearly all chromosomes of cells with elevated levels of FAVL, standardized by control cells (blue line) and elevated levels of FAVL (purple line). Blue and purple lines appearing above or below the yellow line stand for DNA amplification and deletion, respectively. Representative raw data for chromosome 1 and also for chromosome Y (essentially negative, consistent with the origin of U2OS cells) are provided (Supplemental Figure 6A). (B–D) The chromosomal spreads were prepared by using U2OS stable cell pairs, and typical FA-like chromosomal abnormalities were highly associated with U2OS cells expressing FAVL at a high level. The population of U2OS cells overexpressing FAVL (B) has a higher percentage of FA-like chromosomal changes compared with control cells with empty vectors (C), with or without mitomycin C treatment. There are broken, triradial, and quadriradial chromosomes in FAVL-overexpressed cells (B), which are cytogenetic features of FA cells. These tumor cells carry a considerable amount of aneuploidy spreads, which remained similar between 2 types of cells. Original magnification, ×1,000. (D) Average percentage of FA-like chromosomal spreads ± SEM (n = 3).