Knockdown of CUL4A inhibits invasion and induces apoptosis in osteosarcoma cells

Abstract

Cullin4A (CUL4A) is implicated in many cellular events including cell survival and growth. However, the specific function and underlying mechanisms of CUL4A in cancer invasion have not yet been elucidated. In this work, we were focused on investigating the role of CUL4A in human osteosarcoma (OS). The expression level of CUL4A was evaluated by immunohistochemical (IHC) assay in human OS tissues. Lentivirus-mediated CUL4A shRNA (Lv-shCUL4A) constructed by us was transfected into OS cells for assessing its effects on cell proliferation and invasive potential, respectively detected by MTT and Transwell assays. It was demonstrated that the expression of CUL4A protein was markedly increased in OS tissues compared with the adjacent non-cancerous tissues (ANCT) (57.8% vs. 25.6%, P = 0.019), and was associated with the distant metastases in OS patients (P = 0.016). In vitro, silencing of CUL4A gene inhibited OS cell proliferation and invasion, and induced cell apoptosis, followed by increased expression of p27 and p53 and decreased expression of MMP-2. Therefore, these findings indicate that elevated expression of CUL4A is positively correlated with distant metastases in OS patients, and knockdown of CUL4A suppresses invasion and induces apoptosis in OS cells, suggesting that CUL4A may serve as a potential target for the treatment of OS.

Cullin 4A (CUL4A), a direct target of miR-9 and miR-137, promotes gastric cancer proliferation and invasion by regulating the Hippo signaling pathway

“…Besides being involved in the ubiquitin-proteasome pathway, CUL4A is a transcriptional co-activator mediating EGFR and ZEB1 activation, which can promote cancer cell proliferation and EMT through epigenetic mechanisms [ 6 , 7 ]. Recent data support that the high expression of CUL4A is associated with adverse clinical outcomes in several cancer types, including breast, lung, and bone cancer [ 6 – 8 ]. However, the involvement of CUL4A in GC and the mechanisms that regulate its expression remain poorly characterized.…”

Chromatin-Bound Cullin-Ring Ligases: Regulatory Roles in DNA Replication and Potential Targeting for Cancer Therapy

“…Deregulation of CUL4A leads to tumorigenesis in transgenic mice (Jia et al, 2017 ) and the CUL4A locus is often amplified in many human cancers, including hepatocellular carcinomas, pleural mesotheliomas, breast and prostate cancers, squamous cell carcinoma, adrenocortical carcinoma, medulloblastoma, and ovarian invasive carcinoma (Sharma and Nag, 2014 and references therein). CUL4A overexpression in cancer is associated with tumor size, cell proliferation, migration, invasion, and cancer aggressiveness (Song et al, 2015 ; Deng et al, 2016 ; Ren et al, 2016 ; Jia et al, 2017 ; Nagel et al, 2017 ). In addition, CUL4A silencing can inhibit cell proliferation and invasion, and induce cell apoptosis.…”

“…In addition, CUL4A silencing can inhibit cell proliferation and invasion, and induce cell apoptosis. These processes are concomitant with increased expression of p53 and p27 and decreased expression of the metastasis—associated matrix metalloproteinase MMP-2 (Song et al, 2015 ). CUL4A involvement in tumorigenesis may be directly linked to its pivotal roles in the degradation of tumor suppressors or proto-oncogenic proteins associated with growth regulation, including p21, p73, p150/Sal2 and RASSF1A, N-and c-Myc and c-Jun (Sharma and Nag, 2014 ; Song et al, 2015 ).…”

The role and mechanism of CRL4 E3 ubiquitin ligase in cancer and its potential therapy implications

“…Overexpression of CUL4A/B has been demonstrated in many types of cancers [ 9 - 12 , 21 , 22 ], and is associated with a poor prognosis of patient survival [ 15 , 20 ]. Moreover, knockdown of CUL4A/B inhibits the growth of cancer cells [ 16 , 91 , 116 , 117 ], while CUL4A/B overexpression promotes malignant proliferation [ 14 , 21 , 118 , 119 ]. Given these facts, CRL4 may be a potential target for cancer therapy.…”