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Published on: May 14, 2016
Tumor suppressor BLU exerts growth inhibition by blocking ERK signaling and disrupting cell cycle progression through
Xiangning Zhang1, Song-Jun Shao2, Jia-Hui Zhou1,3
1Department of Pathophysiology, Chinese American Collaborative Cancer Research Institute, Guangdong Provincial Key Laboratory of Molecular Diagnostics, Guangdong Medical University Dongguan, Guangdong, People's Republic of China.
Abstract:
We have previously reported that the 3p21 tumor suppressor BLU regulates cell cycle by blocking JNK/MAPK signaling. Another member of the MAPK family, extracellular signal response kinase (ERK), is induced by the RAS-RAF-MEK-ERK pathway and is targeted in anticancer therapy. The effects of BLU on tumor growth were evaluated by measuring the size of nasopharyngeal carcinoma (NPC) xenografted tumors intra-tumorally injected with BLU adenovirus 5 (BLU Ad5) and the viability of NPC cells transferred with BLU. Tumor size was correlated with downregulation of the ERK pathway by BLU. Phosphorylation of ERK and Elk reporter activities were assayed. The regulated cyclins D1 and B1 were measured by CCND1 and CCNB1 gene promoter activity by co-transfection of BLU, RAS V12G, together with BLU+RAS V12G, pCD316+RAS V12G. The cell cycle phase distribution was determined by FACS-based DNA content assay. The data showed that growth of the xenografted tumor was inhibited and viability of HONE-1 cells was reduced by recombinant BLU. BLU down-regulated ERK signaling by reducing protein substrate phosphorylation, inhibiting Elk reporter activity, and blocking promoter activities of the CCND1 gene and reduced cyclins D1 expression to arrest the cell cycle at the G1 phase. The population of G2/M cells was also remarkably decreased. HRAS V12G activated ERK and cyclin D1 and B1 promoters, and the effects were antagonized by BLU. Taken together, our results suggested that BLU inhibited ERK signaling, downregulated cyclins D1 and B1, and prevented cell cycle progression through interfering with HRAS V12G signaling to exert tumor suppression.
Insights
The tumor suppressor BLU inhibits nasopharyngeal carcinoma growth by blocking the ERK pathway, downregulating cyclins D1 and B1, and arresting the cell cycle. This action interferes with HRAS V12G signaling, demonstrating BLU's tumor suppressive role.
Area of Science:
- Molecular Biology
- Oncology
- Cell Signaling
Background:
- The 3p21 tumor suppressor BLU (also known as ZNF238) has been previously shown to regulate the cell cycle by inhibiting JNK/MAPK signaling.
- Extracellular signal-regulated kinase (ERK), a key component of the RAS-RAF-MEK-ERK pathway, is a validated target in anticancer therapy.
- Understanding the interplay between BLU and the ERK pathway is crucial for developing novel therapeutic strategies against cancers like nasopharyngeal carcinoma (NPC).
Purpose of the Study:
- To investigate the effects of BLU on tumor growth and cell viability in nasopharyngeal carcinoma (NPC).
- To elucidate the molecular mechanisms by which BLU influences the ERK signaling pathway and cell cycle progression.
- To determine if BLU can antagonize oncogenic HRAS V12G signaling in the context of NPC.
Main Methods:
- Evaluation of NPC xenograft tumor growth following intra-tumoral injection of BLU adenovirus 5 (BLU Ad5).
- Assessment of NPC cell viability after BLU gene transfer.
- Analysis of ERK pathway activity, including ERK phosphorylation and Elk reporter activity.
- Quantification of cyclin D1 and B1 expression via promoter activity assays and Western blotting.
- Cell cycle phase distribution analysis using Fluorescence-Activated Cell Sorting (FACS).
Main Results:
- Recombinant BLU significantly inhibited xenograft tumor growth and reduced NPC cell viability.
- BLU downregulated ERK signaling by decreasing substrate phosphorylation and inhibiting Elk reporter activity.
- BLU blocked the promoter activities of CCND1 and CCNB1, leading to reduced cyclin D1 and B1 expression, causing G1 cell cycle arrest and decreasing G2/M phase populations.
- Oncogenic HRAS V12G activated ERK and cyclin D1/B1 promoters, effects which were antagonized by BLU.
Conclusions:
- BLU functions as a tumor suppressor in nasopharyngeal carcinoma by inhibiting the ERK signaling pathway.
- BLU downregulates cyclins D1 and B1, leading to cell cycle arrest at the G1 phase.
- BLU exerts its tumor-suppressive effects, in part, by interfering with HRAS V12G-mediated signaling.
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