HDAC8

Official Full Name

histone deacetylase 8

Organism

Homo sapiens

GeneID

55869

Background

Histones play a critical role in transcriptional regulation, cell cycle progression, and developmental events. Histone acetylation/deacetylation alters chromosome structure and affects transcription factor access to DNA. The protein encoded by this gene belongs to class I of the histone deacetylase family. It catalyzes the deacetylation of lysine residues in the histone N-terminal tails and represses transcription in large multiprotein complexes with transcriptional co-repressors. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]

Synonyms

HD8; WTS; RPD3; CDA07; CDLS5; KDAC8; MRXS6; HDACL1;

Bio Chemical Class

Carbon-nitrogen hydrolase

Protein Sequence

MEEPEEPADSGQSLVPVYIYSPEYVSMCDSLAKIPKRASMVHSLIEAYALHKQMRIVKPKVASMEEMATFHTDAYLQHLQKVSQEGDDDHPDSIEYGLGYDCPATEGIFDYAAAIGGATITAAQCLIDGMCKVAINWSGGWHHAKKDEASGFCYLNDAVLGILRLRRKFERILYVDLDLHHGDGVEDAFSFTSKVMTVSLHKFSPGFFPGTGDVSDVGLGKGRYYSVNVPIQDGIQDEKYYQICESVLKEVYQAFNPKAVVLQLGADTIAGDPMCSFNMTPVGIGKCLKYILQWQLATLILGGGGYNLANTARCWTYLTGVILGKTLSSEIPDHEFFTAYGPDYVLEITPSCRPDRNEPHRIQQILNYIKGNLKHVV

Open

Disease

Solid tumour/cancer

Approved Drug

Clinical Trial Drug

1 +

Discontinued Drug

Cat.No.	Product Name	Price

Cat.No.	Product Name	Price

Cat.No.	Product Name	Price

Cat.No.	Product Name	Price

Detailed Information

HDAC8 belongs to class I HDACs depending on its amino acid composition and enzymatic action. First discovered as a nuclear protein, this enzyme resides on chromosome Xq13.1. Depending on the kind of cell and its environment, however, it has been discovered in both the nuclear and cytoplasmic areas. X-ray crystallography revealed the structure to be zinc-dependent in its catalytic action and head-to-head dimer formation. How the enzyme interacts with other chemicals, including potassium ions, which help maintain its structure stable, also influences its function.

HDAC8 influences more than just histones; it also influences non-histone targets. Controlling gene synthesis and maintaining cell function depends much on it. Processes of phosphorylation governed by AMP-activated protein kinase (AMPK) may alter its location inside cells, hence altering its biological activities in various cell environments.

Figure 1 shows the control techniques of human HDAC8. It indicates how transcription factors may increase its level while miRNA, autophagy, and proteasomes can decrease it. Figure 1. Schematic representation of human HDAC8 and its regulation. (Kim JY, et al., 2022)

Role in Cancer Progression

By promoting tumor cells to grow, HDAC8 significantly influences how cancer spreads; it also speeds up spreading and reduces treatment sensitivity in cancer cells. It alters various biological pathways that enable tumor cells to escape death and continue proliferating. Many malignancies show later stages of illness and a worse prognosis associated with high levels of HDAC8. Genetic alteration or medication targeting of HDAC8 to stop these processes has shown promise as a means of cancer control.

Mechanism of Action

By deacetylating key substrates, HDAC8 helps malignancies develop by altering protein function and interconnection. One kind of cancer where HDAC8 alters the JAK2/STAT pathway by modifying the SOCS proteins is myeloproliferative neoplasms. Health depends on its impact on non-histone proteins including mutant and wild-type p53. Blocking HDAC8 in some cancers restores p53 acetylation, hence activating apoptosis and halting tumor development.

Metastasis and Drug Resistance

Utilizing processes including epithelial-mesenchymal transition (EMT), HDAC8 plays a key role in metastasis influencing factors including SNAIL and AKT signaling. Changing YAP, which is part of the Hippo pathway, helps breast cancer spread. HDAC8 is also linked to drug resistance since it interacts with cell processes to reduce the efficacy of medications such as temozolomide and paclitaxel. It seems that combining HDAC8 inhibitors with conventional therapies might help to circumvent these resistance mechanisms.

HDAC8 Beyond Cancer: Broader Biological Implications

HDAC8 influences many non-cancerous illnesses including heart and lung disorders. In cardiac hypertrophy, HDAC8 alters pathways like AKT/GSK-3β and p38 MAPK that promote undesirable heart growth. In heart failure models, blocking it has been shown to reduce cardiac stress. Similarly, HDAC8 alters KLF2 synthesis, which is essential for maintaining lung health. Blocking HDAC8 has shown potential in reversing fibrotic alterations occurring in lung illnesses.

Neurological and Muscular Disorders

HDAC8 is involved in neurological conditions characterized by inflammation and myopathies such as Duchenne muscular dystrophy (DMD). Inhibition of HDAC8 shows therapeutic benefits by restoring muscle function and reducing inflammation. Additionally, HDAC8's role in regulating essential cellular pathways provides a basis for its involvement in genetic disorders like fibrous dysplasia and inflammatory conditions in joints, opening new avenues for therapeutic interventions.

Therapeutic Potential of HDAC8 Inhibitors

Targeting HDAC8 medically calls for certain inhibitors such as PCI-34051 and BMX. Research has shown that these medications are advantageous in many ways, including cancer-fighting and heart-protecting. They also combat inflammation and fibrosis. They improve the efficacy of present medications, assist in overcoming resistance, and provide a targeted approach to managing non-cancer diseases.

Though several medications are now in the human trial phase, HDAC8-selective inhibitors are still under development. They are excellent candidates for further research and therapeutic use as they are very particular and may be employed in many other ways.

References:

Seto E, Yoshida M. Erasers of histone acetylation: the histone deacetylase enzymes. Cold Spring Harb Perspect Biol. 2014;6(4):a018713. Published 2014 Apr 1.
Kim JY, Cho H, Yoo J, et al. Pathological Role of HDAC8: Cancer and Beyond. Cells. 2022;11(19):3161. Published 2022 Oct 9.

Quick Inquiry

Interested in learning more?

Contact us today for a free consultation with the scientific team and discover how Creative Biogene can be a valuable resource and partner for your organization.

Request a quote today!

Inquiry