CYLD

Official Full Name

CYLD lysine 63 deubiquitinase

Organism

Homo sapiens

GeneID

1540

Background

This gene is encodes a cytoplasmic protein with three cytoskeletal-associated protein-glycine-conserved (CAP-GLY) domains that functions as a deubiquitinating enzyme. Mutations in this gene have been associated with cylindromatosis, multiple familial trichoepithelioma, and Brooke-Spiegler syndrome. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

Synonyms

EAC; MFT; SBS; TEM; BRSS; CDMT; MFT1; CYLD1; CYLDI; USPL2; FTDALS8;

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Detailed Information

Recent Research Progress

The cylindromas (headscarcinoma syndrome; CYLD) gene is located at 16q12.1 and encodes a cytoplasmic protein that contains three cytoskeleton-associated proteins-glycine-conserved (CAP-GLY) domain, which acts as a deubiquitinating enzyme. CYLD mutations are associated with Brooke-Spiegler syndrome, familial cylindrical tumor disease and multiple familial epithelial tumors, and were originally described as different genetic diseases characterized by various skin-attached tumors. CYLD is also considered to be a negative regulator of nuclear factor-κB (NF-κB) activity and acts as a tumor suppressor gene in several types of cancer.

CYLD and CRC

It was reported that miR-454 expression was significantly up-regulated in colorectal cancer (CRC) tissues and CRC cells compare to matched tumor adjacent tissues and FHC normal colon cell lines. Ectopic expression of miR-454 promoted proliferation and anchorage-independent growth of CRC cells, whereas inhibition of miR-454 reduces this effect. Bioinformatics analysis further revealed CYLD, a putative tumor suppressor as a potential target for miR-454. Data from the luciferase reporter assay showed that miR-454 directly binds to the 3'-untranslated region (3'-UTR) of CYLD mRNA and inhibits expression at the transcriptional and translational levels. In functional assays, CYLD silencing in miR-454-in-transfected SW480 cells have positive effect to promote cell proliferatio, suggesting that direct CYLD down-regulation is required for miR-454-induced CRC cell proliferation. In summary, these data provide convincing evidence that miR-454 acts as an onco-miRNA and plays a key role in promoting cell proliferation in CRC, and its oncogenic effect is primarily mediated through direct inhibition of CYLD expression.

CYLD and MM

Deletion or mutation of the gene encoding the deubiquitinating enzyme CYLD is a common genomic aberration in multiple myeloma (MM). Current studies show that CYLD expression is highly variable in myeloma cell lines and primary MM, and that low CYLD expression is associated with disease progression from monoclonal gammopathy of undetermined significance to MM, and with poor overall and progression free-survival of MM patients. Functional assays showed that CYLD inhibited MM cell proliferation and survival. Furthermore, CYLD acts as a negative regulator of NF-κB and Wnt/β-catenin signaling and loss of CYLD sensitizes MM cells to NF-kappa B-stimuli and Wnt ligands. Interestingly, in primary MM, low CYLD expression was strongly associated with proliferation and Wnt signaling gene expression characteristics, but not with NF-κB target gene characteristics. Taken together, the current findings identify CYLD as a negative regulator of NF-κB and Wnt/β-catenin signaling in MM and suggest that CYLD deletion enhances MM invasiveness through Wnt pathway activation. Therefore, targeting the Wnt pathway may be a promising therapeutic strategy in MM with a loss of CYLD activity.

CYLD and GC

Gastric cancer (GC) is one of the most common malignancies in the world. Recently, studies have found that the level of miR-130b was significantly up-regulated in GC tissues, compared to paired adjacent non-tumor gastric tissues. The level of miR-130b in GC cell lines was significantly higher than that in control normal gastric tissues. Bioinformatics analysis indicated that CYLD was a potential target gene for miR-130b. Luciferase activity assays and western blots confirmed that miR-130b targets CYLD messenger RNA (mRNA) to modulate its protein levels. In conclusion, studies have demonstrated that aberrantly expressed miR-130b may regulate apoptosis and proliferation of human GC cells via CYLD.

CYLD and cervical cancer

Cervical cancer is a common gynecological fatal malignancy worldwide. The study found that miR-501 was up-regulated compared to normal cervical tissue, while CYLD protein is down-regulated in cervical cancer tissue. Overexpression of miR-501 and down-regulation of CYLD protein were poorly correlated with poor differentiation, tumor size, International Federation of Gynecology and Obstetrics (FIGO) stage and lymph node metastasis. In HeLa cells, miR-501 overexpression and CYLD protein down-regulation were positively correlated with poor CYLD was down-regulated by miR-501 at both messenger RNA (mRNA) and protein levels. MiR-501 promotes proliferation, migration and invasion of cervical cancer cells and inhibits apoptosis. MiR-501 may promote the proliferation, migration and invasion of cervical cancer cells by down-regulating CYLD and subsequently activating NF-κBp65.

CYLD and OSCC

Oral squamous cell carcinoma (OSCC) is a malignant tumor with a poor prognosis, largely due to its aggressive characteristics. The levels of CYLD and SMAD7 in OSCC specimens were reported to be significantly reduced compared to paired normal tissues. Metastatic OSCC appears to contain lower levels of CYLD and SMAD7. In addition, CYLD and SMAD7 levels are closely related in OSCC specimens. Low CYLD levels are associated with low patients' survival. Furthermore, SMAD does not regulate CYLD, but CYLD regulates the level of SMAD7 in OSCC cells. Furthermore, CYLD overexpression inhibits SMAD7-mediated cell invasion, whereas CYLD depletion increases SMCC7-mediated cell invasion in OSCC cells. In conclusion, inhibition of CYLD in OSCC cells may contribute to SMAD7-mediated cancer invasion. Therefore, CYLD appears to be an interesting therapeutic target for preventing OSCC metastasis.

In conclusion, CYLD is hypothesized as a possible target gene for multiple miRs and is a tumor suppressor gene in different types of cancer. Therefore, further study of the role of CYLD in cancer development mechanisms will provide new insights into the diagnosis and treatment of related cancers.

References:

Huang DeHao, et al. MiR-501-5p regulates CYLD expression and promotes cell proliferation in human hepatocellular carcinoma. Japanese Journal of Clinical Oncology, 2015, 45(8): 738–744.
Fang Ni, et al. MicroRNA-362-5p promotes tumor growth and metastasis by targeting CYLD in hepatocellular carcinoma, Cancer Letters, 2015, 356(2): 809-818.
Liang, HongLiang, et al. MiR-454 prompts cell proliferation of human colorectal cancer cells by repressing CYLD expression. Asian Pacific journal of cancer prevention, 2015, 6(16): 2397-402.
van Andel H, et al. Loss of CYLD expression unleashes Wnt signaling in multiple myeloma and is associated with aggressive disease. Oncogene, 2017, 36(15): 2105-2115.
Yang YF, et al. MiR-425-5p promotes tumor progression via modulation of CYLD in gastric cancer. European Review for Medical and Pharmacological Sciences, 2017, 21(9): 2130-2136.
Sun BY, et al. MiR-130b inhibits proliferation and induces apoptosis of gastric cancer cells via CYLD. Tumor Biology, 2016, 37(6): 7981-7987.
Sanches JGP, et al. miR-501 is upregulated in cervical cancer and promotes cell proliferation, migration and invasion by targeting CYLD. Chemico-Biological Interaction, 2018, 285: 85-95.
Ge WeiLi, et al. Regulation of Oral Squamous Cell Carcinoma Proliferation Through Crosstalk Between SMAD7 and CYLD. Cell Physiol Biochem, 2016, 38:1209-1217.

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