Dysregulation of the miR-194-CUL4B negative feedback loop drives tumorigenesis in non-small-cell lung carcinoma.
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.
The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Molecular Medicine and Genetics, Shandong University School of Basic Medical Sciences, Jinan, China.|Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Shandong University School of Stomatology, Jinan, China.
Jun
J
Mi
The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Molecular Medicine and Genetics, Shandong University School of Basic Medical Sciences, Jinan, China.
Yongxin
Y
Zou
The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Molecular Medicine and Genetics, Shandong University School of Basic Medical Sciences, Jinan, China.
Xiaohua
X
Lin
The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Molecular Medicine and Genetics, Shandong University School of Basic Medical Sciences, Jinan, China.
Juanjuan
J
Lu
The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Molecular Medicine and Genetics, Shandong University School of Basic Medical Sciences, Jinan, China.
Xiaochen
X
Liu
The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Molecular Medicine and Genetics, Shandong University School of Basic Medical Sciences, Jinan, China.
Hui
H
Zhao
The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Molecular Medicine and Genetics, Shandong University School of Basic Medical Sciences, Jinan, China.
Xiang
X
Ye
The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Molecular Medicine and Genetics, Shandong University School of Basic Medical Sciences, Jinan, China.
Huili
H
Hu
The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Molecular Medicine and Genetics, Shandong University School of Basic Medical Sciences, Jinan, China.
Baichun
B
Jiang
Department of Pathology, Shandong University School of Basic Medical Sciences, Jinan, China.|Department of Pathology, Shandong University Qilu Hospital, Jinan, China.
Bo
B
Han
The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Molecular Medicine and Genetics, Shandong University School of Basic Medical Sciences, Jinan, China.|Department of Genetics/Human Genetics Institute of New Jersey, Piscataway, NJ, USA.
Changshun
C
Shao
The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Molecular Medicine and Genetics, Shandong University School of Basic Medical Sciences, Jinan, China.
Yaoqin
Y
Gong
D000818:Animals; D063646:Carcinogenesis / Q000235:genetics* / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology; D044842:Cullin Proteins / Q000032:analysis / Q000235:genetics*; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology*; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000032:analysis / Q000235:genetics*; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology
C517832:CUL4B protein, human; D044842:Cullin Proteins; C554846:MIRN194 microRNA, human; D035683:MicroRNAs
CUL4B; H2AK119 monoubiquitination; double-negative feedback loop; lung cancer; microRNA