Pharmacologic researchers develop a novel alkylating chemotherapeutic agent against glioblastoma multiforme. They find that malignant cells with methylation of the promoter region for the O6-methylguanine-DNA methyltransferase (MGMT) gene are more susceptible to this drug than cells without methylation. Which of the following is the most likely function of the protein encoded by the gene?
Neoplasms develop genetic alterations that promote cellular growth and survival. Although this is partially mediated by inactivating genetic mutations in tumor suppressor genes (eg, p53), much of oncogenesis is mediated by the altered expression of unmutated genes, as follows:
Histone modification: Chromatin is organized into nucleosomes, which consist of a segment of DNA wrapped around 8 histone proteins. Modification of histones via acetylation, phosphorylation, or methylation can alter the availability of DNA for transcription, leading to increased or decreased gene expression. Histone modification allows tumors to increase prosurvival gene expression and reduce cell cycle arrest/apoptosis gene expression.
Transcription factor expression: Transcription factors are activated by cell-surface ligand binding or by phosphorylation. Activated transcription factors travel to the nucleus and bind to the promoter/enhancer region of a specific gene, which alters RNA polymerase binding and subsequent gene expression. Tumors overexpress surface receptors (eg, HER2) that generate pro-survival transcription factors and underexpress surface receptors that generate cell cycle arrest/apoptotic signals.
CpG modifications: Promoter regions typically contain a section of 200-2000 base pairs that primarily contain a cytosine followed a guanosine. Methylation of the CpG region silences the adjacent gene; neoplasms often methylate CpG promoter regions adjacent to genes that slow growth.
As part of oncogenesis, many glioblastomas methylate the CpG region adjacent to the O6-methylguanine-DNA methyltransferase (MGMT) gene, which generates a protein that repairs damaged DNA (eg, converts O6-methylguanine [a naturally occurring alkylation product] back to guanine). Although silencing MGMT creates a more permissive environment for DNA mutations to drive cancer growth, it also makes the cell more susceptible to alkylating chemotherapy (eg, temozolomide), since alkylating agents cause DNA damage that cannot be effectively repaired without MGMT.
(Choice A) Mutation of tumor suppressing genes (eg, BAX) that trigger apoptosis or cell cycle arrest promotes oncogenesis. However, MGMT is not an apoptotic gene.
(Choice B) As part of oncogenesis, tumors often reduce major histocompatibility complex class I expression, lowering the ability of cytotoxic T cells to recognize the abnormal proteins generated by cancerous cells. This process is not mediated by MGMT.
(Choice D) Increased telomerase activity helps promote cancer cell longevity; telomerase activity is frequently increased in tumors, but it is not mediated by MGMT.
Educational objective:
Cancer cells alter expression of genes controlling survival and replication by histone modification, transcription factor expression, and CpG methylation. Methylation of the CpG region adjacent to the MGMT gene, which produces an enzyme that repairs DNA, makes tumor cells much more susceptible to alkylating chemotherapy.