Histone Demethylase RBP2 Promotes Lung Tumorigenesis and Cancer Metastasis

Abstract

The retinoblastoma binding protein RBP2 (KDM5A) is a histone demethylase that promotes gastric cancer cell growth and is enriched in drug-resistant lung cancer cells. In tumor-prone mice lacking the tumor suppressor gene RB or MEN1, genetic ablation of RBP2 can suppress tumor initiation, but the pathogenic breadth and mechanistic aspects of this effect relative to human tumors have not been defined. Here, we approached this question in the context of lung cancer. RBP2 was overexpressed in human lung cancer tissues where its depletion impaired cell proliferation, motility, migration, invasion, and metastasis. RBP2 oncogenicity relied on its demethylase and DNA-binding activities. RBP2 upregulated expression of cyclins D1 and E1 while suppressing the expression of cyclin-dependent kinase inhibitor p27 (CDKN1B), each contributing to RBP2-mediated cell proliferation. Expression microarray analyses revealed that RBP2 promoted expression of integrin-b1 (ITGB1), which is implicated in lung cancer metastasis. Mechanistic investigations established that RBP2 bound directly to the p27, cyclin D1, and ITGB1 promoters and that exogenous expression of cyclin D1, cyclin E1, or ITGB1 was sufficient to rescue proliferation or migration/invasion, respectively. Taken together, our results establish an oncogenic role for RBP2 in lung tumorigenesis and progression and uncover novel RBP2 targets mediating this role. Cancer Res; 73(15); 4711-21. Ó2013 AACR.

Histone demethylase RBP2 decreases miR-21 in blast crisis of chronic myeloid leukemia

“…or suppressing the expression of cyclin-dependent kinase inhibitor (CDKIs) p21(CIP1), p27(kip1) etc. by altering H3K4 methylation at the promoters of target genes [40, 41]. Here, we provide evidence that RBP2 decreased the expression of miR-21 epigenetically.…”

Histone demethylase RBP2 induced by Helicobactor Pylori CagA participates in the malignant transformation of gastric epithelial cells

“…This molecule should be associated with cell cycle since tumorigenesis is closely related with uncontrolled cell proliferation. Published data showed that Cyclin D1 was a downstream target of RBP2 in lung cancer [23], so we tried to testify this in GC. As can be seen in Figure 5A and 5B, when RBP2 was inhibited in BGC-823 cells, Cyclin D1 expression decreased both at mRNA and protein level, which was in line with the finding in lung cancer.…”

Lysine-Specific Histone Demethylases Contribute to Cellular Differentiation and Carcinogenesis

“…The KDM5 Cluster (JARID1 Subfamily) KDM5A (JARID1A) promotes gastric cancer cell growth and is enriched in drug-resistant lung cancer cells. The depletion of this protein from lung cancer tissues, indeed, drastically affects cell proliferation, motility, migration, invasion, and metastasis [132] In this context, KDM5A binds to integrin-b1 (ITGB1) promoters and induces its expression. Integrin-b1, in turn, plays key roles in lung cancer metastasis.…”

“…Integrin-b1, in turn, plays key roles in lung cancer metastasis. Simultaneously, KDM5A induces the expression of cyclins D1 and E1 while suppressing the expression of cyclin-dependent kinase inhibitor p27 (CDKN1B), each contributing to KDM5A-mediated cell proliferation [132,133]. Besides its roles in gastric and lung cancer, KDM5A has been suggested to contribute, through its interaction with retinoblastoma protein (pRb), to uncontrolled growth in malignant melanomas.…”