Dysregulation of the miR‐194–CUL4B negative feedback loop drives tumorigenesis in non‐small‐cell lung carcinoma

Abstract

Cullin 4B (CUL4B), a scaffold protein that assembles CRL4B ubiquitin ligase complexes, is overexpressed in many types of cancers and represses many tumor suppressors through epigenetic mechanisms. However, the mechanisms by which CUL4B is upregulated remain to be elucidated. Here, we show that CUL4B is upregulated in non‐small‐cell lung carcinoma (NSCLC) tissues and is critically required for cell proliferation and migration in vitro and for xenograft tumor formation in vivo. We found that microRNA‐194 (miR‐194) and CUL4B protein were inversely correlated in cancer specimens and demonstrated that miR‐194 could downregulate CUL4B by directly targeting its 3′‐UTR. We also showed that CUL4B could be negatively regulated by p53 in a miR‐194‐dependent manner. miR‐194 was further shown to attenuate the malignant phenotype of lung cancer cells by downregulating CUL4B. Interestingly, CRL4B also epigenetically represses miR‐194 by catalyzing monoubiquitination at H2AK119 and by coordinating with PRC2 to promote trimethylation at H3K27 at the gene clusters encoding miR‐194. RBX1, another component in CRL4B complex, is also targeted by miR‐194 in NSCLC cells. Our results thus establish a double‐negative feedback loop between miR‐194 and CRL4B, dysregulation of which contributes to tumorigenesis. The function of miR‐194 as a negative regulator of CUL4B has therapeutic implications in lung cancer.

miR‑381 and miR‑489 suppress cell proliferation and invasion by targeting CUL4B via the Wnt/β‑catenin pathway in gastric cancer

“…Previous studies have indicated that some members of the Cullin protein family may be targeted by miRNAs (26,36). Moreover, CUL4B and miR-194 have been found to regulate each other directly in a coordinated manner (10). In the present study, we identified miR-381 and miR-489 as potential regulators of CUL4B using computational prediction tools.…”

“…Cullin 4B (CUL4B) is a scaffold protein responsible for assembling DDB1, RBX1 and substrate component to form the CRL4B ubiquitin ligase complexes (3), contributing to ubiquitin-mediated proteolysis and tumourigenesis (4,5). Mounting evidence has highlighted the upregulation and oncogenic potential of CUL4B in various types of cancer, including hepatocellular carcinoma, lung cancer, colon cancer and bladder cancer (6)(7)(8)(9)(10). Mechanistically, CUL4B epigenetically represses a series of tumour suppressors, including insulin-like growth factor-binding protein 3 (IGFBP3), phosphatase and tensin homolog (PTEN) and p16 through physical interaction with the SIN3A/HDAC and SUV39H1/HP1/DNMT3A complexes (11,12).…”

CUL4B regulates autophagy via JNK signaling in diffuse large B-cell lymphoma

“…As we alluded to above, emerging evidence had identified that CUL4B was highly expressed in different human malignancies, including carcinoma of the cervix, esophagus, liver, gastric and pancreatic cancer, and had a positive correlation with tumor progression [3,8,12,13,31]. Furthermore, CUL4B overexpression was significantly correlated with tumor size, advanced tumor stage, vascular and lymphatic invasion, distant metastasis, and histological differentiation, and was positively correlated with undesirable outcomes [3,[32][33][34].…”

“…Several studies have demonstrated that CUL4B plays significant roles in the invasion, differentiation, and metastasis of carcinogenesis [11][12][13], the involved mechanisms may be related to signaling dysregulation. However, the expression and potential function of CUL4B in DLBCL is unclear.…”

MALAT1 knockdown inhibits hypopharyngeal squamous cell carcinoma malignancy by targeting microRNA‑194

“…cells (22,23). Insulin-like growth factor 1 receptor (IGF1R) and Yes-associated protein 1 (YAP1) have been identified as targets of miR-194 by bioinformatics studies (24,25).…”