Question

Cancer is a genetic disease that arises due mutations in growth promoting genes (oncogenes) and in growth suppressing genes (tumor suppressor genes). Mutations in oncogenes that can lead to cancer are gain-of-function mutations that result in the constitutive activation of the proteins encoded by these genes. An example of such a gene is Ras, a gene mutated in over 90% of pancreatic cancers. When mutated, the Ras signaling is constitutively active, leading to uncontrolled cell growth. Tumor suppressor genes encode proteins whose normal function is to prevent excessive cells proliferation. Mutations in tumor suppressor genes are loss of function mutations. When mutated, they are no longer able to suppress excessive cell proliferation, leading to uncontrolled cell growth. Drugs that inhibit DNA methylation or histone acetylation are often used to treat cancer. Which drug is best to use depends on the nature of the mutated gene driving cancer cell growth.

A. Explain the effect DNA methylation inhibitor of would have on gene expression levels

B. Explain the effect a histone acetylation inhibitor of would have on gene expression levels.

C. For pancreatic cancers driven by mutant Ras, which type of treatment would be a more effective drug to use for treatment, one that inhibits DNA methylation or one that inhibits histone acetylation. Justify your answer.

D. For cancers that are driven by mutations in tumor suppressor genes, would you recommend using the same drug as for oncogene-driven cancers? Why or why not?

Answer 1

A. DNA methylation is a gene regulatory mechanism that controls the transcription of the target genes without modifying the DNA sequence. DNA methylation does not allow the transcription factor to bind on the DNA to initiate transcription. DNA methylation inhibitor drugs would prevent DNA methylation and thus, activate the genes.

B. Histone acetylation is the acetylation of the lysine residue on the N terminal of the histone proteins. The acetylation of the histone proteins removes the positive charge and thus reduces their affinity for the negatively charged DNA molecule, which exposes the DNA to the transcription factors. The acetylation thus promotes the transcription of DNA. The histone acetylation inhibitor would thus prevent DNA expression.

C. For pancreatic cancers, the histone acetylation inhibitors would be more effective, since it would prevent the expression of the genes involved in the Ras signaling.

D. For cancers caused by the mutations in the tumor suppressor genes, the DNA methylation inhibitors would be more effective. DNA methylation inhibitors would activate the tumor suppressor genes.