Grape seed proanthocyanidins reactivate silenced tumor suppressor genes in human skin cancer cells by targeting epigenetic regulators

Skin Cancer

Skin Cancer
Long-term sun exposure can result in skin cancer. Malignant melanoma is the deadliest form of skin cancer. Ultraviolet radiation (UVR) is a proven human carcinogen.24 The sun emits three types of harmful rays
UVA UVB UVC

Types of Ultraviolet Rays

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Skin Cancer
The major factor in skin cancer formation is sun exposure Skin type is also important in dictating how the skin reacts to the sun
Pale Celtic skin is most at risk Dark afrocaribean skin is least at risk

X-ray

UVB UVC UVA 100-280 280-315 315-400

Visible Light 400-700

Stratosphere - Ozone Layer

Dead Sea Level

Sea Level

Definition of Skin Cancer:

Cancer that forms in tissues of the skin. Skin cancer begins in cells, the building blocks that make up our skin. Normally, skin cells grow and divide to form new cells. Every day skin cells grow old and die, and new cells take their place. When this orderly process goes wrong new cells form when the skin does not need them, and old cells do not die when they should. They form growths or tumors which can be benign or malignant.

Skin Cancer
Not all races have an equal risk of developing skin cancer Skin cancers overwhelmingly develop in white people The following slide has the incidences of NMSC in different races in different parts of the world The highest incidence found was in white Australian men living in tropical Queensland The incidence in coloured people was lower, even when they lived in the tropics.

Malignant skin tumors: Genetic factors: Xeroderma pigmentosum, neurofibroma may change to neurofibrosarcoma. Enviromental factors: Ultraviolet light is the most important factor especially in those with fair skin. Tar, arsenic, mineral oils. X-ray: diagnostic or therapeutic. Long standing scars, fistulas, sinuses. Viruses: Burkuit lymphoma ----------- EBV HPV may cause Ca cervix Kaposi sarcoma is thought to be caused by herpes simplex virus- 8. Drugs: long lasting use of immunosuppressant like azathioprime, cyclophosphamide, cyclosporine or even steroids.

Skin cancer represents approximately two to four percent of all cancers in Asians.36

Skin cancer comprises one to two percent of all cancers in African Americans and Asian Indians. 36
Melanomas in African Americans, Asians, Filipinos, Indonesians, and native Hawaiians most often occur on non-exposed skin with less pigment, with up to 6075 percent of tumors arising on the palms, soles, mucous membranes and nail regions.36 Basal cell carcinoma (BCC) is the most common cancer in Caucasians, Hispanics, Chinese Asian and the Japanese.36 Squamous cell carcinoma (SCC) is the most common skin cancer among African Americans and Asian Indians.36 Squamous cell carcinomas in African Americans tend to be more aggressive and are associated with a 20-40 percent risk of metastasis (spreading).36

Types of Skin Cancers

Copyright 2010 Pearson Education, Inc.

Types of Skin Cancer

Melanoma-forms in melanocytes (skin cells that make pigment). Basal Cell Carcinoma-forms in basal cells (small, round cells in the base of the outer layer of skin). Squamous cell carcinoma-forms in squamous cells (cells that form the surface of the skin).

Skin Cancer
The most common skin cancer is the Basal Cell Carcinoma (BCC) The next most common is the Squamous Cell Carcinoma (SCC) The least common is the Melanoma (MM) BCC and SCC are often grouped together as non-melanoma skin cancer (NMSC)

Basal Cell Carcinomas

Commonest skin cancer in Caucasian populations Major cause is sun exposure Common sites on face and trunk Not metastatic

Squamous cell carcinoma

Second most common skin cancer in Caucasian populations Caused by sun exposure - chronic sun exposure Most at risk are those with pale skin who burn in the sun Commonest on sun exposed areas Pre-cancerous lesion is the solar keratosis Metastatic potential - to regional lymph nodes, then liver, lungs etc

Melanoma
Third most common skin cancer Caused by severe intermittent bouts of sun exposure Found on sun exposed and non-exposed sites Second most common cancer to affect young women High metastatic potential - local, lymph nodes, lung, liver and brain

Melanoma
30% arise in a pre-existing mole
Features to look out for are asymmetry of the mole, irregular shape and irregular colour

Most commonly arise in normal skin in renal transplant patients

Tumor Suppressor Genes

Cancer Usually Involves Several Genes

Tumor suppressor genes
Stop cell growth and division; prevent cancer formation May prevent expression of oncogenes p53: codes for a regulatory protein that turns off cell division when the cell is stressed or damaged
If mutated, runaway cell division More than half of cancers has a mutated or missing p53 gene

Types of cancer genes

Type of gene
Oncogene

Normal function
Promotes division

Mutated function
Promotes division abnormal time or cell type Fails to suppress division

Types of proteins
Growth factors

Tumor suppressor gene DNA repair gene mutation

Suppresses cell division

Checkpoint molecules

Repair DNA mutations

Fail to repair DNA mutations

Enzymes for mismatch or excision repair

Epigenetics
Epigenetics - On or over the genetic information encoded in the DNA

 Skin cancer is the manifestation of a series of genetic and epigenetic events. Epigenetic processes result in heritable phenotypical changes in gene expression that do not involve alterations in the actual DNA sequence. Involve variations in DNA methylation, chromatin structure or microRNA proles The hallmarks of epigenetic gene regulation are DNA methylation and histone modications. Reversible and can be manipulated pharmacologically,

 Epigenetic inactivation of genes by promoter hypermethylation has been recognized as an important mechanism by which tumor suppressor genes are shut down during development of cancers

Epigenetics
The study of reversible heritable changes in gene function that occur without a change in the sequence of nuclear DNA Gene-regulatory information that is not expressed in DNA sequences is transmitted from one generation (of cells or organisms) to the next

Epigenetics and Different Aspects of Life

Development of multicellular organism Environment-organism interaction
For examples: Nutrition supplements and environmental toxins

Image: Randy Jirtle

Pathogenesis of diseases

Molecular Mechanisms that Mediate Epigenetic Phenomena

DNA methylation (CpG dinucleotides) Histone modifications

Nucleosome

Epigenetic Regulation of Gene Expression

Epigenetic information modulates gene expression without modifying actual DNA sequence Histone modifications change the chromatin structure and affect the accessibility of DNA to regulatory proteins

Epigenetic Regulation of Gene Expression

Methylated DNA Histone

Histone Modification Status Correlates with Transcriptional Activity

Gene activation correlated with H3-K9 acetylation Gene silencing associated with H3-K9 methylation

Epigenetic Inheritance
Transmission of non-DNA sequence information through either meiosis or mitosis When a methylated DNA sequence replicates, only one strand of the next-generation double helix has all its methyl markers intact; the other strand needs to be remethylated Maintenance methylase theory
DNA methyltransferases (DNMTs): Enzymes that bind methyl groups to cytosine nucleotides DNMTs bind methyl groups to the naked cytosines based on the methylation template provided by the other strand-

Epigenetics and Cancer

Chromosomal infrastructure is essential for gene control, determining both active and repressed states It is important not only to turn the right genes on but also to turn the right genes off Histones and chromatin components have key roles in this decision making process If as few as three inappropriate genes are turned off, a normal cell can be converted into a cancer cell This epigenetic silencing of genes underlies a new approach to cancer therapy Mistargeting of these enzymes leads to tumorigenesis, but inhibition of their activity presents a novel approach to therapy

Grape seed proanthocyanidins