FAVL elevation in human tumors disrupts Fanconi anemia pathway signaling and promotes genomic instability and tumor growth.
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.
Zhang
Jun
J
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota 55905, USA.
Zhao
Deping
D
Park
Hwan Ki
HK
Wang
Hong
H
Dyer
Roy B
RB
Liu
Wanguo
W
Klee
George G
GG
McNiven
Mark A
MA
Tindall
Donald J
DJ
Molina
Julian R
JR
Fei
Peiwen
P
D000818:Animals; D001483:Base Sequence; D002277:Carcinoma / Q000196:embryology*; D002869:Chromosome Aberrations; D018450:Disease Progression; D005199:Fanconi Anemia / Q000378:metabolism*; D052240:Fanconi Anemia Complementation Group L Protein / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D042822:Genomic Instability; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009368:Neoplasm Transplantation; D012689:Sequence Homology, Nucleic Acid; D015398:Signal Transduction
C499908:FANCL protein, human; D052240:Fanconi Anemia Complementation Group L Protein
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