Cancer Gene Activation/Deactivation

Viruses and Cancer

  • Viruses can cause cancer by regulating oncogenes and tumor suppressor genes (TSGs).

  • Epigenetic regulation plays a role in cancer.

  • Non-coding RNA can promote cancer growth.

  • Viruses can integrate into the host cell genome and cause cancer.

Mechanism of Viral Oncogenesis

  • Viral DNA integrates into the host genome.

  • If the viral genome contains an oncogene, it can be expressed in the host, causing cell transformation.

Examples of Tumor Viruses

  • DNA Viruses:

    • Hepatitis B virus (HBV)

    • Human Papilloma virus 16/18 (HPV)

  • RNA Viruses:

    • Rous sarcoma virus (RSV)

    • Human T cell leukemia virus (HTLV-1)

  • Mechanisms:

    • Direct: Activation of proto-oncogenes or inactivation of TSGs.

    • Indirect: Chronic immune response.

Common Cellular Targets for Tumor Virus Oncoproteins

  • Rb

  • p53

  • PI3K-mTOR-Akt

  • Interferon

Insertional Mutagenesis

  • Viruses lacking oncogenes can transform cells through insertional mutagenesis.

  • Example: Avian leukosis virus (ALV).

    • ALV integrates its genome adjacent to the c-myc proto-oncogene.

    • Transcription is regulated by the ALV viral promoter, leading to enhanced transcription and growth promotion.

  • Insertional mutagenesis causing cancer has not been reported in humans but has been observed in other vertebrates (e.g., chickens).

Epigenetics and Gene Expression

  • Epigenetics provides a non-mutagenic way to regulate gene expression.

  • Involves altering gene activity without modifying the DNA code.

  • May cause gene silencing or gene activation.

  • Effects are reversible.

  • Mechanisms:

    • DNA promoter methylation

    • Histone methylation

    • Histone deacetylation

Epigenetic Mechanisms

  • Writers: DNA methyltransferases transfer a methyl group to Cytosine DNA residues, resulting in promoter hypermethylation and gene silencing.

  • Erasers: DNA demethylases remove the methyl group.

  • Readers: Methyl-CpG-binding domain proteins recruit chromatin remodelers, histone deacetylases, and methylases.

DNA Methylation

  • Methylation commonly occurs in CpG islands in gene promoter regions.

  • Methylation causes closed chromatin structures, silencing gene expression.

MLH1 Silencing and Microsatellite Instability

  • MLH1 is a DNA mis-match repair protein often silenced in Colorectal, Gastric, and Endometrial Cancer.

  • Methylation of the MLH1 promoter can block transcription factor binding, leading to silencing of MLH1 expression.

  • This is known as mis-match repair deficiency (MMRd).

  • Instability in microsatellite DNA leads to major errors in the genome that promote carcinogenesis. Microsatellite instable (MSI) cancers are paradoxically good responders to immunotherapy, as the instability leads to many neoantigens recognized by the immune system for destruction.

Hypermethylation of Tumor Suppressor Genes

  • Hypermethylation of tumor suppressor genes is common in cancer.

  • Examples of hypermethylated genes found in human tumor cell genomes:

Non-coding RNA

  • Only 2% of the genome encodes proteins. The remainder encodes important RNA regulatory molecules.

  • In cancer, long non-coding RNA (lncRNA) and miRNA are often associated with cancer.

lncRNA in Cancer

  • Hypermethylated in cancer = silenced.

  • Hypomethylated in cancer = activated.

  • EPIC1 is a lncRNA overexpressed in luminal B breast cancer.

  • EPIC1 promotes cell cycle progression by interacting with MYC protein.

Summary

  • Viral oncogenes can integrate into host DNA, causing elevated expression of oncogenes and loss of function of TSGs.

  • Epigenetic mechanisms modify gene expression without altering the DNA code through chemical marks (methylation, acetylation) that alter chromatin structure.

  • Non-coding RNAs may contribute to cancer progression through direct and indirect regulatory mechanisms.