ZNF238 is expressed in postmitotic brain cells and inhibits brain tumor growth

Area of Science:

• Neuro-oncology
• Molecular Biology
• Cancer Genetics

Background:

• Brain tumors, including medulloblastoma (MB) and glioblastoma multiforme (GBM), can originate from neural precursors.
• The uncontrolled proliferation of cerebellar granule neuron precursors (GNP) is implicated in MB development.
• The precise gene functions that regulate precursor proliferation arrest and differentiation in brain tumors remain largely unknown.

Purpose of the Study:

• To identify genes that are suppressed in brain tumors but normally promote neural precursor differentiation and proliferation arrest.
• To investigate the role of ZNF238 in neural precursor differentiation and its potential as a brain tumor suppressor.

Main Methods:

• Expression analysis of ZNF238 in proliferating vs. postmitotic GNPs, and in MB and GBM cells.
• Functional studies involving inhibition or re-expression of ZNF238 in mouse GNPs and brain tumor cells.
• Assessment of cell cycle markers (p27, cyclin D1) and neuronal differentiation markers (MAP2, NeuN).
• In vivo xenograft studies to evaluate ZNF238's effect on tumor growth.

Main Results:

• ZNF238 is highly expressed in postmitotic neurons and differentiated GNPs, but low or absent in proliferating GNPs, MB, and GBM.
• Inhibition of ZNF238 in GNPs reduced neuronal differentiation markers and cell cycle arrest protein p27.
• Reinstating ZNF238 in MB and GBM cells decreased proliferation, induced cell death, downregulated cyclin D1, and increased MAP2 and p27.
• ZNF238 significantly inhibited MB and GBM tumor growth in vivo xenografts.

Conclusions:

• ZNF238 functions as an antiproliferative factor in normal neural precursors and acts as a novel brain tumor suppressor.
• Reactivation of ZNF238 in brain tumors represents a potential novel anticancer strategy.