Table 1.
Dysregulation and mutation of HDACs in human cancer.
| Cancer types | HDACs | Prognostic relevance | Genetic evidence | Molecular mechanism | References |
|---|---|---|---|---|---|
| Solid Tumours | |||||
| 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 | Upregulated 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; Minamiya et al. 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 | Upregulated 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 | Upregulated 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 upregulates miR-449 and downregulates c-MET expression. 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 | Upregulation is correlated with DNA copy number gains. | N/A | N/A | (Lachenmayer et al. 2012) | |
| HDAC5 | Upregulated in HCC tissues. | Knockdown of HDAC5 promotes cell apoptosis and inhibits tumor cell growth in vitro and in vivo. | HDAC5 knockdown promotes apoptosis by upregulating cyto C, caspase 3, p53 and bax, and induces G1 phase cell cycle arrest by upregulating p21 and downregulating cyclin D1 and CDK2/4/6. | (Fan et al. 2014) | |
| HDAC5 | Upregulated 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 suppress HCC cell apoptosis, and promote 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 towards etoposide in PDAC cells. | HDAC2 knockdown upregulates NOXA expression which sensitize tumor cells towards 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; Ouaissi et al. 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 | Upregulated 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 ER-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 downregulating 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 | Upregulation of HDAC2, 8 and downregulation 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 over expression 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 upregulated 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. 2014) | |
| 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) |
Human hepatocellular carcinoma (HCC), Pancreatic ductal adenocarcinoma (PDAC), Acute lymphoblastic leukemia (ALL), Chronic lymphocytic leukemia (CLL), Acute myelogenous leukemia (AML), Diffuse large B-cell lymphoma (DLBCL), Cutaneous T-cell lymphomas (CTCL), Hodgkin’s lymphoma (HL).