Table 1.
Histone deacetylases and its potential implications in cancer
| Classification (class-wise) | HDAC | Localization | Histone protein/substrate association | Non-histone substrates | Expression in cancer | Stages in cancer/function | Functional involvement | HDACi | References |
|---|---|---|---|---|---|---|---|---|---|
| I | HDAC1 | Nucleus | HDAC2 | RB1, p53, CtIP, CoREST, SHP, BCL6, AMPK, AML1-ETO, Sin3, MyoD, NuRD, PML, PLZF, E2F1, NF-κB, STAT3 | ↑ Gastric; breast; colorectal; lung; HL and liver cancer | Cell proliferation, angiogenesis | Knockdown promotes growth arrest, less viability, induces apoptosis and genomic instability | Tacedinaline, quisinostat, abexinostat, romidepsin, depsipeptide, pracinostat, ricolinostat, entinostat, mocetinostat, tubastatin A | [17, 18, 20, 72] |
| HDAC2 | Nucleus | HDAC1 | CoREST, Sin3, STAT3, AML1-ETO, GCCR, PML, PLZF, BCL6, YY1 | ↑ Gastric; colorectal; HL and prostate cancer | Cell proliferation, angiogenesis, differentiation | Quisinostat, abexinostat, romidepsin, ricolinostat, pracinostat, mocetinostat | [15, 20, 29–31, 72] | ||
| HDAC3 | Nucleus | HDAC4, HDAC5, HDAC7 | NCoR/SMR, SHP, AML1-ETO, NF-κβ GATA1/2, RARα, PML, PLZF, PML–PLZF–RARα, Bcl6, YY1, 2p65, MEF2D STAT1/3 |
↑ Gastric; breast; ALL; HL and colorectal cancer ↓ Liver cancer |
Cell proliferation, angiogenesis, differentiation |
Knockdown helps in relieved transcription repression in APL cells by PML–RARα Induces apoptosis and decreases cell viability while knockdown |
Quisinostat, abexinostat, pracinostat, resminostat, ricolinostat, mocetinostat, entinostat, droxinostat | [20, 35, 37, 38, 73, 74, 132] | |
| HDAC8 | Nucleus | – | SMC3, actin | ↑ Neuroblastoma | Cell proliferation | Reduced proliferation in cervical, lung and colon cancer due to knockdown | Quisinostat, ricolinostat, pracinostat, droxinostat, tubastatin A | [133] | |
| II a | HDAC4 | Nucleus/cytoplasm | HDAC3–NCor | GATA1, HP1 | – | Cell proliferation, angiogenesis, and differentiation |
Induction of apoptosis and decreased cell viability in colon cancer and glioblastoma Increased VEGF expression in chondrosarcoma |
Quisinostat, pracinostat, tasquinimod, CUDC-101/907, TMP269 | [54, 81, 134] |
| HDAC5 | Nucleus/cytoplasm | HDAC3–NCor | GATA1, GATA2, SMAD7, HP1 |
↑ Medulloblastoma ↓ Lung cancer |
Differentiation | Increased cell growth and viability upon overexpression | Quisinostat, pracinostat, LMK-235, TMP269, CUDC-101/907, ricolinostat | [6, 15, 54, 134] | |
| HDAC7 | Nucleus/cytoplasm | HDAC3–NCor | PLAG1, PLAG2, ERα |
↑ ALL ↓ Lung cancer |
Differentiation | Suppresses cell growth arrest in colon and breast cancer | Quisinostat, pracinostat, TMP269, CUDC-101/907, ricolinostat | [133] | |
| HDAC9 | Nucleus/cytoplasm | – | Bcl-2, IL-3, CEBPA, PU.1, c-fms, BPI | ↑ ALL and medulloblastoma | Differentiation | Overexpression decreases sensitivity to DNA damage and increases medulloblastoma cell growth and viability | TMP269, CUDC-101/907, quisinostat, pracinostat | [133] | |
| II b | HDAC6 | Cytoplasm | HDAC11 | α-Tubulin, HSP90, SHP, SMAD |
↑ Breast cancer ↓ Lung cancer |
Differentiation and angiogenesis | Knockdown decreases cell viability and VEGF expression | Tubacin, nexturastat A, TSA, HPOB, resminostat, pracinostat, droxinostat, CAY10603 | [82, 86, 96] |
| HDAC10 | Nucleus | – | – | – | DNA repair |
Overexpression makes less sensitive to DNA damage Overexpression increases VEGF expression |
CUDC-101/907, quisinostat, PCl-24781, HPOB | [70, 97] | |
| III | SIRT1 | Nucleus/cytoplasm | HDAC1, H3K9 H3K14 H3K56 H4K16 H1K26 | p53, β-catenin, Ku70, E2F1, Rb, NF-κB, PGC1α, AKT, PPARγ, MYC, MyoD, PCAF, FOXO3, LXR, HIF1α, ATG5, ATG7, ATG8, SMAD7, FXR, RARβ, SREBP1C/2 |
↓ Lymphoma; colon, liver and lung cancer ↑ Prostate and thyroid cancer |
Chromatin regulation, transcription, DNA repair and metabolism |
Overexpression attenuates apoptosis, promotes DNA repair and genomic stability, suppresses β-catenin-mediated cell proliferation Knockdown induces loss of BRCA1 in breast cancer, inhibits anti-apoptotic genes |
Tenovin-6, BDF4-1, -2a, -2b, -2d, salermide, nicotinamide, JGB-1741, cambinol, EX527, AC-93253, aristoforin, inauhzin, Tenovin-1, Tenovin-6 | [33, 34, 37, 60, 63, 78, 79, 135] |
| SIRT2 | Cytoplasm | H4K16, H3K56, H3K18 | α-Tubulin, HIF1α, PRLR, FOXO1/3A, keratin 8, PAR3, p300, NF-κβ | ↑ Mammary gland; skin and hepatocellular carcinoma | Metabolism, cell cycle and differentiation | Sirt2 knockout results in genomic instability, higher expression of mitotic activators and increased at G2/M expression | Tenovin-6, BDF4-1, -2a, -2b, -2d, salermide, AGK2, aristoforin, nicotinamide, sirtinol, cambinol, AC-93253, AK-7, Tenovin-1, Tenovin-6 | [65, 95, 118, 135] | |
| SIRT3 | Nucleus/mitochondria | H4K16 | IDH2, SDH, CypD, OPA1, FOXO3A, PDH, LCAD, p53, MRPL10, GDH, LKB1, VLCAD, OTC, GOT2, PDP1, Ku70, SKP2, SOD2, NDUFA9, ACECS2, HMGCS2 | ↓ Mammary gland cancer | Metabolism |
Sirt3-null cells exhibit genomic instability Deletion causes breast, ovarian, lung cancer and medulloblastoma Overexpression causes OSCC growth |
AC-93253, Tenovin-6, LC-0296 | [39, 43, 80, 83, 84, 135] | |
| SIRT4 | Mitochondria | SIRT3 | ANT2/3, GDH, MCD, PDH SLC25A5, IDE | ↓ Lung; lymphoma and small epitopic tumors | Metabolism |
Loss of SIRT4 accelerates MYC induced lymphomas Overexpression induces cell death Downregulation sensitizes toward small cell lung carcinoma, gastric, bladder and breast cancer |
Nicotinamide | [67, 135] | |
| SIRT5 | Mitochondria | – | CPS1, cytochrome c, HMGCS2, PDH, SDH, SOD1, GAPDH | ↑ Non-small cell lung carcinoma and smaller epitopic tumors | Metabolism | Overexpression causes non-small cell lung carcinoma | Nicotinamide, cambinol | [98, 135] | |
| SIRT6 | Nucleus | H3K9, H3K56 | NF-κB, DNA CtBP, HIF1α, PARP1, MYC, TNF, SREBP1, PK SREBP2, CtIP USP10, GCN5, SNF2H, G3BP, FOXO3 | ↓ Larger epitopic tumors; larger intestinal tumors; liver and pancreatic cancer | Chromatin and DNA repair |
Downregulation causes colon, hepatocellular and rectal adenocarcinoma Inhibition of SIRT6 expression regulates anti-apoptotic genes Causes resistance to chemotherapy by enhancing DNA damage in breast cancer Promotes angiogenesis and metastasis in pancreatic cancer |
Nicotinamide, OSS-128167 | [135] | |
| SIRT7 | Nucleolus | H3K18 | p53, mTOR, MYC, PAF53, HIF1α, HIF2α, ELK4, TFIIIC2, RNA Pol I, MYBBP1A | ↓ Smaller ectopic tumors | Transcription and metabolism | Overexpression causes uncontrolled cell growth and loss of contact inhibition in uterine, colon, kidney, ovarian and prostate cancer | – | [135] | |
| IV | HDAC11 | Nucleus/cytoplasm | HDAC6 | – | ↑ Breast; renal and liver cancer | Transcription and cell cycle regulation | Over expression inhibits apoptosis in breast, colon, prostate and ovarian cancer | Mocetinostat, pracinostat, quisinostat, CUDC-907 | [133] |