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Histone Deacetylases-Leanne Wentz

Page history last edited by Christopher Korey 14 years, 10 months ago

Histone Deacetylases-Leanne Wentz

 

HISTONE DEACETYLASE

a cause of cancer?

 

 

Histone Deacetylase

 

BACKGROUND

    The classical  HDACs seem to resemble the make up of yeast such as Saccharomyces cerevisiae (Ruijter et al., 2003).  They contain a tubular pocket, zinc binding site, and two asparagine-histidine relay systems that are important in it's function so are very affected when blocked HDAC inhibitors (Kim et al, 2002). Histone Deacetylases function to remove acetyl groups from histone tails which tightens the bonds between the histone lysines and the DNA phosphate backbone leaving no room for proteins necessary for transcription.

 

HDAC Complexes:

     There are many different complexes which can come about for histone deacetylase which aid in the repression of transcription.  One example is the corepressor Sin3 which binds to both HDAC1 and HDAC2 families as well as other proteins such as RbAp46, RbAp48, and SAP30 (Kuzmichev et al., 2002).  To read more about this complex click the previous link and learn the role it plays and how they observed the complex.  NuRD(nucleosome remodeling and deacetylating) and co-REST are the two more complexes using HDAC1 and HDAC2 (Ruijter et al, 2003).  Histone deacetylases work in complexes to more efficiently silence expression and repress transcription through attraction of HDACs to promoters.  Complexes are essential and different ones occur for each family.

     


CLASSES:

Total of four classes and 18 family subsets of histone deacetylase in the human genome.  Classes 1, 2, and 4 are known as classical HDACs (Witt et al, 2008).

     Class 1:  This class of Histone deacetylase consists of families 1, 2, 3, and 8 (Witt et. al, 2008). They are similar in that they have a single catalytic domain and are expressed within all tissues (Chen and Cepko, 2007).  These are found almost exclusively in the nucleus (Ruijter et al, 2003). HDAC1 and HDAC2 are structurally similar as well as HDAC3 and HDAC8 (Ruijter et al., 2003).  

     Class 2: These are further divided into IIa and IIb and include families 4(Converse, 2000),5(Converse,2000), 7(Converse, 2001), and 9(Converse, 2001) which are separated because of their big N-terminus domain for IIA (Glaser et al., 2003).  Subfamilies 6 and 10 are for class IIb( Witt et al., 2008). HDAC6 is different from the rest because it consists of two catalytic domains and a zinc finger domain (Han et al., 2009).  To view more information on the particular protiens click on the links next to them.  Class 2 all contain a N-terminus and C-terminus catalytic domains (Chen and Cepko, 2007).  

     Class 4: Includes only number 11 which affects the core histone to regulate gene expression (Hartz, 2002

     Class 3:  Is separated from all the other classes because it works differently.  These histone deacetylases work through metabolism and are usually found inside the nucleolus mostly in higher eukaryotes (Khochbin et. al., 2001).

 

Witt et al., 2008


 

HISTONE DEACETYLASE IN GENE EXPRESSION:

 

     Many nucleosomes holding together to form chromatin greatly hinders transcription because it is harder to detach DNA to transcribe (Vermeulen et al., 2006).  Histone deacetylase (HDAC) works against the Histone acetyltransferase (HAT) regulating whether DNA binds tightly to these histones which make up each nucleosome thought to work through an equilibrium (Vermeulen et al., 2006).  HDAC can be recruited by methyl CpG-binding proteins, such as MeCP2, causing the histone to lose acetyl groups leaving a negative charge to attract the negative DNA backbone and repress transcription (Robertson et al., 2000).  Histone lysine is what is enzymatically acetylated /deacetylated by the two opposing proteins (Vermeulen et al., 2006). HDACs have also been found to play a role in transcription factor repression by blocking sites, and recently an activator as well by attracting factors to the protein (Chen and Copka, 2007), (Bode et al., 2007).The activity of HDAC occurs mainly through complexes depending on the type as mentioned earlier and cannot really do it by itself.      

Figure shows possible equilibrium of Histone acetyltransferase and the histone deacetylases.( Cook, 2007 )


 

HOW HISTONE DEACETYLASE CONTRIBUTES TO CANCER:

 

     A decrease in monoacetylation and trimethylation in the histone H4 have shown to increase the amount of tumor cells (Ozdag et al., 2006).  Because HDAC as mentioned in the last section has been found to oppose acetylation it is reasonable to relate HDAC to the increase in cancer cells also.  HDACs are not the only causes of tumors and each cancer or tumor includes different mechanisms of growth (Ozdag et al., 2006).  HDACs are associated with cancer in that they can repress transcription of tumor suppressor genes allowing the tumor to grow without hinderance (Zhoa et al., 2003).  Without the tumor supressor genes no messages from RNA will occur to prevent the growth of the tumor or cancer cells.  The video below should help visualize this occurance and help introduce how Inhibitors of HDAC can help reduce this transcriptional repressions of tumor suppressor genes.

 

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HISTONE DEACETYLASE INHIBITORS

     HDAC inhibitors are used to stop the growth of tumor cells as visualized in the video above.  There are different inhibitors that are specific for particular types of Histone Deacetylases.  I will explain three main ones used below, but there are more than this, especially as research progresses and more effective ones are being found. 

  •   Vorinostat (SAHA)- SAHA is marketed under the name Zolinza for treatment of cutaneous T cell lymphoma (CTCL) and is a broad inhibitor of HDAC (Wikipedia, 2008). SAHA actually attatches to the zinc binding site of the HDAC (Finnin et al., 1999).  The you tube video above shows a visual of this HDAC inhibitor.                                                                                                                                                                                                                                                                                                                                                                                 (Wikipedia, 2008)                                       
  •   Valproic Acid (VPA)- Originally used for epilepsy and mood disorders, VPA inhibit HDACs in a dose dependent manner (Condorelli et al., 2008). This molecule was able to preserve p53 acetylation on lysines in experiments done by Condorelli et al. on neuroblastoma stabilizing it's activation conformation.  This HDAC inhibition likely occurred in the mitochondrial pathway (Condorelli et al., 2008).                                                                        (Wikipedia, 2008)
  •   Trichostatin A (TSA)- TSA is know as a common reversible inhibitor of HDAC activity (Balakrishnan and Milavetz, 2008).  TSA inhibits class 1 and 2 of HDACs by altering the ability of transcription factors to bind inside the chromatin (Wikipedia, 2008).  Anticancer drug uses are to promote expression of apoptosis related genes or to induce cell differentiation possibly "maturing" cancer cells so wont reproduce (Wikipedia, 2008)                                                                            (Wikipedia, 2008)

 

 

SUMMARY:

Overall HDAC's are important transcriptional repressors of histones to regulate the expression of genes, but they can get out of hand with too many, possibly repressing tumor suppressor genes increasing the amount of tumor cells being produced.  Because we know this can happen, HDAC inhibitors are being thoroughly studied for all sorts of cancers.  With all the different types of HDACs in many tissues there is many places were these can go wrong just like the amount of cancers.  If we can keep finding specific inhibitors maybe someday we will find away to do more than simply slow down progession as most of the inhibitors do, but truely allow apoptosis to occur to all the carcinogenic cells.  We are coming closer to this, and these inhibitors have helped increase life spans by slowing down the HDACs which are repressing too many important genes. 

 

 

 

 

 

 

 

Comments (1)

Christopher Korey said

at 4:02 pm on Apr 6, 2009

Outline looks good. Each section should be concise and then point to more specific information. For example do not go into amazing detail with each type of deacetylase. Mention that their are 4 types which have differing functions--give an example and then link out to article, book in NIH Book site or another website to provide further information for some one who is interested. I like the black background image and the middle HAT/HDAC figure I would get rid of the others. You tube was not working. Make sure to add in references and reference where images came from. Divide sections with a horizontal bar.

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