Table 1.
Dysregulation and mutation of HDACs in human cancer
| Cancer types | HDACs | Prognostic relevance | Genetic evidence | Molecular mechanism | References |
|---|---|---|---|---|---|
| Solid tumors | |||||
| Neuroblastoma | HDAC8 | High transcript level correlates with advanced-stage disease and poor survival in neuroblastoma | Knockdown and inhibition of HDAC8 promotes cell-cycle arrest and differentiation, delays cell growth, and induces cell death in vitro and in vivo | HDAC8 inhibition induces p21WAF1/CIP1 and NTRK1/TrkA gene expression and enhances retinoic acid-mediated differentiation by regulating CREB phosphorylation | Oehme et al. 2009; Rettig et al. 2015 |
| HDAC10 | High expression correlates with poor overall patient survival in advanced INSS stage 4 neuroblastoma | Knockdown and inhibition of HDAC10 in neuroblastoma cells interrupted autophagic flux resulting in an increase of sensitization to cytotoxic drug treatment | HDAC10 controls autophagic processing and resistance to cytotoxic drugs via interaction with Hsp70 family proteins | Oehme et al. 2013 | |
| Medulloblastoma | HDAC2 | Overexpressed in medulloblastoma subgroups with poor prognosis | HDAC2 depletion induces cell death and attenuates cell growth; MYC amplified and HDAC2 overexpressing cell lines are more sensitive to class I HDACi | N/A | Ecker et al. 2015 |
| HDAC5, 9 | Up-regulated in high-risk medulloblastoma, and their expression is associated with poor survival | Depletion of either HDAC5 or HDAC9 in MB cells resulted in a reduction of cell proliferation and increase in cell death | N/A | Milde et al. 2010 | |
| Lung | HDAC1, 3 | High expression correlates with a poor prognosis in patients with lung adenocarcinoma | N/A | N/A | Minamiya et al. 2010, 2011 |
| HDAC2 | Abundant expression is observed in lung cancer tissues | HDAC2 inactivation represses tumor cell growth in vitro and in vivo | HDAC2 depletion activates apoptosis via p53 and Bax activation and Bcl2 suppression induces cell-cycle arrest by induction of p21 and suppression of cyclin E2, cyclin D1, and CDK2 | Jung et al. 2012 | |
| HDAC5, 10 | Low expression is associated with poor prognosis in lung cancer patients | N/A | N/A | Osada et al. 2004 | |
| Gastric | HDAC1, 2, 3 | High expression is associated with nodal tumor spread and decreased overall patient survival | N/A | N/A | Weichert et al. 2008b; Sudo et al. 2011 |
| HDAC4 | Up-regulated in gastric tumor cells compared with adjacent normal tissues | HDAC4 inhibition has a synergistic effect with docetaxel treatment | HDAC4 inhibition increased the level of cleaved caspases 3 and 9 | Colarossi et al. 2014 | |
| HDAC10 | Low expression is a poor prognosis marker for gastric cancer patients | N/A | N/A | Jin et al. 2014 | |
| Liver | HDAC1 | Highly expressed in human HCCs and liver cancer cell lines | HDAC1 inactivation impairs G1/S cell-cycle transition and causes autophagic cell death | Knockdown of HDAC1 induces p21 and p27 expression and suppresses cyclin D1 and CDK2 expression | Xie et al. 2012 |
| HDAC1, 2, 3 | Up-regulated in human HCCs and liver cancer cell lines | The knockdown of HDAC1–3 leads to increased apoptosis and decreased proliferation | Knockdown and inhibition of HDAC1–3 up-regulates miR-449 and down-regulates c-MET expression, and reduced c-MET dephosphorylates ERK1/2 and inhibits tumor growth | Buurman et al. 2012 | |
| HDAC1, 2, 3 | High expression is associated with poor survival in low-grade and early-stage tumors | N/A | N/A | Quint et al. 2011 | |
| HDAC3, 5 | Up-regulation is correlated with DNA copy number gains | N/A | N/A | Lachenmayer et al. 2012 | |
| HDAC5 | Up-regulated in HCC tissues | Knockdown of HDAC5 promotes cell apoptosis and inhibits tumor cell growth in vitro and in vivo | HDAC5 knockdown promotes apoptosis by up-regulating cyto C, caspase 3, p53, and bax, and induces G1 phase cell-cycle arrest by up-regulating p21 and down-regulating cyclin D1 and CDK2/4/6 | Fan et al. 2014 | |
| HDAC5 | Up-regulated in human HCC tissues | Overexpression of HDAC5 promotes tumor cell proliferation, while knockdown of HDAC5 inhibits cell proliferation | HDAC5 promotes cell proliferation by up-regulation of Six1 | Feng et al. 2014 | |
| HDAC6 | Low expression is associated with poor prognosis in liver transplantation patients | Knockdown of HDAC6 promotes HUVEC migration, proliferation, and tube formation in vitro, and suppresses HCC cell apoptosis and promotes HCC cell proliferation in hypoxia | HDAC6 knockdown promotes angiogenesis in HCC by HIF-1α/VEGFA axis | Lv et al. 2015 | |
| Pancreatic | HDAC2 | Highly expressed in PDAC | HDAC2 confers resistance toward etoposide in PDAC cells | HDAC2 knockdown up-regulates NOXA expression, which sensitizes tumor cells toward etoposide-induced apoptosis | Fritsche et al. 2009 |
| HDAC6 | Highly expressed in human pancreatic cancer tissues | Knockdown and inhibition of HDAC6 impairs the motility of cancer cells | HDAC6 interacts with CLIP-170 and stimulates the migration of pancreatic cancer cells | Li et al. 2014 | |
| HDAC7 | Overexpression is associated with poor prognosis | Knockdown of HDAC7 inhibits tumor cell growth | N/A | Ouaissi et al. 2008, 2014 | |
| Colorectal | HDAC2 mutation | Truncating mutations are found in microsatellite unstable sporadic colorectal cancers, which lead to a loss of expression of the protein | HDAC2 mutation renders cells more resistant to antiproliferative and proapoptotic effects of the HDAC inhibitor | N/A | Ropero et al. 2006 |
| HDAC1, 2, 3 | Highly expressed in a subset of colorectal carcinomas; HDAC2 is an independent prognostic factor in colorectal carcinoma | Knockdown of HDAC1 and HDAC2 but not HDAC3 suppresses tumor cell growth | N/A | Weichert et al. 2008d | |
| HDAC1, 2, 3, 5, 7 | Up-regulated in human colorectal cancer; HDAC2 is an early biomarker of colon carcinogenesis | N/A | N/A | Stypula-Cyrus et al. 2013 | |
| Breast | HDAC1, 2, 3 | HDAC1 was highly expressed in hormone receptor-positive tumors; HDAC2 and 3 are highly expressed in poorly differentiated and hormone receptor negative tumors | N/A | N/A | Zhang et al. 2005; Muller et al. 2013 |
| HDAC1, 6 | High expression is good prognostic factors for estrogen-receptor-positive invasive ductal carcinomas | N/A | N/A | Zhang et al. 2004; Seo et al. 2014 | |
| Ovarian | HDAC1, 2, 3 | High expression is associated with a poor outcome | Knockdown of HDAC1 reduces cell proliferation via down-regulating cyclin A expression, and knockdown of HDAC3 reduces the cell migration with elevated E-cadherin | Hayashi et al. 2010 | |
| HDAC1, 2, 3 | High-level expression is associated with a poor prognosis in ovarian endometrioid carcinomas | N/A | N/A | Weichert et al. 2008a | |
| Cervical | HDAC10 | Low expression correlates with lymph node metastasis in cervical cancer | Knockdown of HDAC10 promotes cervical cancer cell migration and invasion | HDAC10 inhibits MMP2 and -9 expression | Song et al. 2013 |
| Prostate | HDAC1, 2, 3 | Highly expressed in prostate carcinomas HDAC2 is an independent prognostic marker in prostate cancer cohort | N/A | N/A | Weichert et al. 2008c |
| Renal | HDAC1, 2 | Highly expressed in renal cell cancer, but none of them are associated with patient survival | N/A | N/A | Fritzsche et al. 2008 |
| Bladder | HDAC1, 2, 3 | High expression is associated with higher tumor grades; high HDAC1 is a poor prognostic factor in urothelial bladder cancer | N/A | N/A | Poyet et al. 2014 |
| HDAC2, 4, 5, 7, 8 | Up-regulation of HDAC2, 8 and down-regulation of HDAC4, 5, and 7 mRNA are observed in urothelial cancer | N/A | N/A | Niegisch et al. 2013 | |
| Melanoma | HDAC3, 8 | HDAC8 was increased in BRAF-mutated melanoma; HDAC8 and 3 overexpression are associated with improved survival of patients with stage IV metastatic melanoma | N/A | N/A | Wilmott et al. 2015 |
| Hematological tumors | |||||
| ALL | HDAC1–9 | HDAC2, 3, 6, 7, 8 are up-regulated in ALL samples; HDAC1 and 4 show high expression in T-ALL and HDAC6 and 9 are highly expressed in B-lineage ALL; higher expression of HDAC7 and 9 is associated with a poor prognosis in childhood ALL | N/A | N/A | Moreno et al. 2010 |
| HDAC4 | High expression is associated with high initial leukocyte count, T cell ALL and prednisone poor response | HDAC4 knockdown enhanced etoposide’s cytotoxic activity | N/A | Gruhn et al. 2013 | |
| CLL | HDAC1, 3, 6, 7, 9, 10, SIRT1 and 6 | Higher expressions are associated with poor prognosis and more advanced disease stage | N/A | N/A | Wang et al. 2011 |
| HDAC6, 7, 10 and SIRT2, 3, 6 | Overexpression of HDAC7 and 10 and underexpression of HDAC6 and SIRT3 are correlated with a poor prognosis | N/A | N/A | Van Damme et al. 2012 | |
| AML | HDAC5, 6, SIRT1 and 4 | HDAC6 and SIRT1 are overexpressed, and HDAC5 and SIRT4 are underexpressed in AML samples | N/A | N/A | Bradbury et al. 2005 |
| DLBCL | HDAC1 | Highly expressed in cases of DLBCL and correlated with a poor survival | N/A | N/A | Min et al. 2012 |
| HDAC2 | Highly expressed in nodal lymphomas, which is associated with shorter survival | N/A | N/A | Lee et al. 2014b | |
| HDAC1, 2, 6 | The expression is higher in cases of DLBCL or PTCL; high HDAC6 level is associated with favorable outcome in DLBCL, but with a negative outcome in PTCL | N/A | N/A | Marquard et al. 2009 | |
| HDAC3 | Overexpression is observed in phospho STAT3-positive ABC-type DLBCL | HDAC3 knockdown inhibited survival of pSTAT3-positive DLBCL cells | HDAC3 knockdown unregulated STAT3Lys685 acetylation but prevented STAT3Tyr705 phosphorylation | Gupta et al. 2012 | |
| CTCL | HDAC2, 6 | HDAC2 is highly expressed in aggressive rather than indolent CTCL; HDAC6 is associated with a favorable outcome independent of the subtype | N/A | N/A | Marquard et al. 2008 |
| HL | HDAC1, 2, 3 | Overexpressed in HL tissue samples; high HDAC1 expression is correlated with a worse outcome | N/A | N/A | Adams et al. 2010 |
| Myeloma | HDAC1 | Overexpression of class I HDAC, particularly HDAC1, is associated with poor prognosis in myeloma | N/A | N/A | Mithraprabhu et al. 2014 |
HCC, Human hepatocellular carcinoma; PDAC, pancreatic ductal adenocarcinoma; ALL, acute lymphoblastic leukemia; CLL, chronic lymphocytic leukemia; AML, acute myelogenous leukemia; DLBCL, diffuse large B-cell lymphoma; CTCL, cutaneous T-cell lymphomas; HL, Hodgkin’s lymphoma.