@Article{096504020X15861709922491,
AUTHOR = {Ting La, Lei Jin, Xiao Ying Liu, Ze Hua Song, Margaret Farrelly, Yu Chen Feng, Xu Guang Yan, Yuan Yuan Zhang,† Rick F. Thorne,*§ Xu Dong Zhang,  Liu Teng},
TITLE = {Cylindromatosis Is Required for Survival of a Subset of Melanoma},
JOURNAL = {Oncology Research},
VOLUME = {28},
YEAR = {2020},
NUMBER = {4},
PAGES = {385--398},
URL = {http://www.techscience.com/or/v28n4/48521},
ISSN = {1555-3906},
ABSTRACT = {The deubiquitinase cylindromatosis (CYLD) functions as a tumor suppressor inhibiting cell proliferation in 
many cancer types including melanoma. Here we present evidence that a proportion of melanoma cells are 
nonetheless addicted to CYLD for survival. The expression levels of CYLD varied widely in melanoma cell 
lines and melanomas in vivo, with a subset of melanoma cell lines and melanomas displaying even higher 
levels of CYLD than melanocyte lines and nevi, respectively. Strikingly, although short hairpin RNA (shRNA) 
knockdown of CYLD promoted, as anticipated, cell proliferation in some melanoma cell lines, it reduced 
cell viability in a fraction of melanoma cell lines with relatively high levels of CYLD expression and did 
not impinge on survival and proliferation in a third type of melanoma cell lines. The decrease in cell viability caused by CYLD knockdown was due to induction of apoptosis, as it was associated with activation of 
the caspase cascade and was abolished by treatment with a general caspase inhibitor. Mechanistic investigations demonstrated that induction of apoptosis by CYLD knockdown was caused by upregulation of receptorinteracting protein kinase 1 (RIPK1) that was associated with elevated K63-linked polyubiquitination of the 
protein, indicating that CYLD is critical for controlling RIPK1 expression in these cells. Of note, microRNA 
(miR) profiling showed that miR-99b-3p that was predicted to target the 3 -untranslated region (3 -UTR) of 
the CYLD mRNA was reduced in melanoma cell lines with high levels of CYLD compared with melanocyte 
lines. Further functional studies confirmed that the reduction in miR-99b-3p expression was responsible for 
the increased expression of CYLD in a highly cell line-specific manner. Taken together, these results reveal an 
unexpected role of CYLD in promoting survival of a subset of melanoma cells and uncover the heterogeneity 
of CYLD expression and its biological significance in melanoma.},
DOI = {10.3727/096504020X15861709922491}
}