Study on CUL4B , from Mental Retardation to Cancer

CUL4B is first identified as a mental retardation gene in our laboratory. We further confirmed that CUL4B also functions importantly in cancer. In our latest publication, we revealed CUL4B sustained the oncogenic properties in bladder cancer through regulating miR-372/373-PIK3CA/AKT axis.

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After I joined Prof. Yaoqin Gong’s group to start my PhD training in 2003, I started studying the biological role of CUL4B in Yaoqin’s lab. CUL4B belongs to cullin family, the members of which function as a“scaffold” in cullin-RING-based E3 ubiquitin ligases (CRLs). We firstly identified that loss function mutation in CUL4B gene causes a syndromic X‐linked mental retardation (XLMR)-MRXS15[1]. Like most of the XLMR carriers, the carriers of MRXS15 have no abnormal physical appearance. However, we found the X-chromosome inactivation was extremely skewed in leukocytes of these carriers, suggesting a strong selection against cells expressing the mutant CUL4B allele[1]. Indeed, in the following research, we found CUL4B was required for DNA replication initiation and normal cell proliferation[2, 3].

Considering the importance of deregulation of cell proliferation in cancer, our group further investigated the role of CUL4B in cancer. We uncovered that CUL4B is substantially upregulated in various types of solid tumors, and sustains the oncogenic properties in cancer cells [4-7]. Bladder cancer (BC) is one of the most common malignancy. BC can be classified into non-muscle-invasive BC (NMIBC), and muscle-invasive BC (MIBC). As for MIBC, the 5-year survival rate is less than 50% [8].  While NMIBC is rarely lethal, up to 50-70% cases will recur, and 10-30% will progress to MIBC [8] , the potential of which is highly unpredictable. In our latest publication, we attempted to determine the pathogenic roles and the underlying mechanisms of CUL4B in BC.

We found that CUL4B levels in BC tumor tissues were significantly higher than that in normal tissues and was positively correlated with tumor staging. We then studied the role of CUL4B in BC cell proliferation. Interestingly, though the consistent effects of CUL4B on tumor growth were observed in different BC cell lines in vivo assays by using  tumor xenograft model, the in vitro assays showed the CUL4B only displayed monolayer cell proliferation-promoting activity in low-grade but not in higher-grade and invasive cell lines, indicating that the role of CUL4B in cell proliferation varies in different BC cells. We further demonstrated that CUL4B promoted migration, invasion, stemness and chemoresistance of BC cells through upregulation of AKT signaling, and AKT inhibitor significantly inhibited lung metastasis of CUL4B overexpressed BC cells .

Our lab previously showed that CUL4B positively regulated AKT pathway by repressing AKT associated phosphatase or promoting HER2 expression [4, 6, 9]. Through conducting an abundance of experiments, we confirmed that CUL4B complex catalyzes monoubiquitination of H2AK119 at the promoter of miR-372/373, and, therefore represses transcription of miR-372/373 that directly targets PI3KCA, leading to upregulation of PIK3CA and activation of AKT. Therefore, the underlying mechanisms of upregulation of AKT signaling by CUL4B may vary in different cell types.

 Together, the findings of this study establish a critical role for the CUL4B-miR-372/373-PIK3CA/AKT axis in the pathogenesis of BC, and suggest the drugs targeting AKT may have a more potent effect on BC patients with CUL4B overexpression.  All the steps of our research from identification of mental retardation gene to cancer research demonstrate that we couldn’t know where the research will go, just pursue, persist and enjoy it.

 

1.          Zou Y, Liu Q, Chen B et al: Mutation in CUL4B, which encodes a member of cullin-RING ubiquitin ligase complex, causes X-linked mental retardation. Am J Hum Genet 2007, 80(3):561-566.

2.          Zou Y, Mi J, Cui J et al: Characterization of nuclear localization signal in the N terminus of CUL4B and its essential role in cyclin E degradation and cell cycle progression. J Biol Chem 2009, 284(48):33320-33332.

3.          Zou Y, Mi J, Wang W et al: CUL4B promotes replication licensing by up-regulating the CDK2-CDC6 cascade. J Cell Biol 2013, 200(6):743-756.

4.          Hu H, Yang Y, Ji Q et al: CRL4B catalyzes H2AK119 monoubiquitination and coordinates with PRC2 to promote tumorigenesis. Cancer Cell 2012, 22(6):781-795.

5.          Yuan J, Han B, Hu H et al: CUL4B activates Wnt/β‐catenin signalling in hepatocellular carcinoma by repressing Wnt antagonists. Journal of Pathology 2015, 235(5):784-795.

6.          Qi M, Jiao M, Li X et al: CUL4B promotes gastric cancer invasion and metastasis-involvement of upregulation of HER2. Oncogene 2017, 37(8):1075-1085.

7.          Mi J, Zou Y, Lin X et al: Dysregulation of the miR-194-CUL4B negative feedback loop drives tumorigenesis in non-small-cell lung carcinoma. MOL ONCOL 2017, 11(3):305-319.

8.          MA K, CD H: Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity. Nature Reviews: Cancer 2015, 15(1):25-41.

9.          Qian Y, Yuan J, Hu H et al: The CUL4B/AKT/β-catenin axis restricts the accumulation of myeloid-derived suppressor cells to prohibit the establishment of a tumor permissive microenvironment. Cancer Research 2015, 75(23):5070-5083.

 

Zou Yongxin

asscociate professor, Shandong University School of Basic Medical Sciences

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