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PMCOL 200 > 33 Epigenetic Drugs > Flashcards

33 Epigenetic Drugs Flashcards

1
Q

What are two criteria of epigenetics?

A
  1. Change in gene function without mutation
  2. heritable
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2
Q

What is the difference between Euchromatin and heterochromatin?

A
  • Euchromatin is loosely associated with DNA - Open and accessible - Genes are ON
  • Heterochromatin is closely associated with DNA - closed and inaccessible: Genes off
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3
Q

What are two major types of epigenetic mods?

A
  1. Acetylation
    • adds an acetyl group (CH3-C=O) onto lysine (K) residues of histone proteins
    • Generally activating (euchromatin - open)
      • weakens interaction with DNA via charge neutralization
  2. Methylation
    • associated with silenced gene expression
    • weakens interaction between histones and DNA but can be found in heterochromatin (closed) and euchromatin (open)
    • occurs on all 4 histones
    • Transfer of methyl group to an amino acid on a histone protein - neutralizes charge
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4
Q

What epigenetic alterations might result in cancer?

A

Turning off a tumor suppressor gene (TSG) or turning on an oncogene (promotes cell cycle)

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5
Q

What are HMT’s?

A

Histone Methyltransferases

  • Include members of the SET1 and SUV family
  • enzymes that promote histone methylation by consuming S-adenosyl methionine (SAM) cofactor and producing S-adenosyl homocystein
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6
Q

What are two main classes of histone demethylases?

A
  1. LSD-type
    • flavin adenine dinucleotide (FAD)-dependent amine oxidase
  2. JHD1-type
    • Fe(II) and alpha-KG-dependent hydroxylase

Classes based on the cofactor used

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7
Q

What are examples of histone methylation drugs?

A
  • LSD1 inhibitors
    • Tazemetostat
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8
Q

How does Tazemetostat work?

A

Tazemetostat is an inhibitor of EZH2 histone methyltransferases used to treat hematopoietic malignancies

  • LSD1 inhibitors are being tested in cancer
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9
Q

Histone acetyltransferases are enzymes that use the co-factor ______ and transfer the ______ onto _______ of histones and other proteins

A

Histone acetyltransferases are enzymes that use the co-factor acetyl-CoA and transfer the acetyl from this molecule onto lysine residues of histones and other proteins

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10
Q

What are two major histone acetyltransferases (HAT)?

A

PCAF and P300

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11
Q

What are the three classes of histone deacetylases?

A

Class I

Class II

  • both use Zn2+ to perform the reaction
  • produce deacetylated histone and acetate

Class III

  • Sirtuins
  • Use NAD+ as a co-factor
  • produce nicotinamide, O-Ac-ADPR and deacetylated protein
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12
Q

HDACs?

A

Histone deacetylases

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13
Q

Typically, histone acetylation drugs are designed to inhibit ______ for cancer tx

A

Typically, histone acetylation drugs are designed to inhibit (histone deacetylases) HDAC I and II for cancer tx

  • Reactivate silenced tumor suppressor genes
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14
Q

What is unique about the deacetylation action of Sirtuins?

A

Sirtuins are unique in that they deacetylate not only histones but other proteins also - targets for activation (resveratrol)

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15
Q

What is Vorinostat?

A

drug

Inhibitor of Class I and II Histone deacetylases (HDACs) and is clinically used for the tx of T-cell lymphoma

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16
Q

What is DNA methylation?

A

Addition of methyl at the 5’ position of a cytosine (5mc) base in DNA

  • typically occurs in CpG regions of DNA
  • usually suppressive: turns off transcription by blocking promoter recognition of a TF - can also activate

Eliminated passively during replication

17
Q

What is the role of DNA methyltransferases (Dnmt enzymes)?

A

Catalyze transfer of methyl onto cytosine using SAM (same as in histone methyltransferase) as a cofactor

18
Q

What is Dnmt1?

A

DNA methyltransferase which acts as the “maintenance” to make sure methylation is preserved during cell replication

19
Q

What two DNA methyltransferases can participate in de novo methylation?

A

Dnmt3a and Dnmt3b

20
Q

How does active DNA demethylation occur?

A

Through enzymatic processes:

  • Direct demethylation by
    • activation induced cytidine deaminase (AID)
    • Ten Eleven Translocation (TET) enzymes
21
Q

DNA methylation drugs are typically designed to _______ for cancer tx

A

DNA methylation drugs are typically designed to inhibit Dnmt enzymes for cancer tx

  • Dnmt = DNA methyltransferase enzymes
22
Q

What is Decitabine?

A

Pharmacological inhibitor of Dnmts (DNA methyltransferases) which has been used in cancer tx

23
Q

How might vitamin C be considered a DNA methylation drug?

A

Vit C is a natural activator of the TET DNA demethylases

(TET = ten eleven translocation enzymes)

PMCOL 200 (30 decks)

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