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  • For various cancer types HDAC

    2018-11-01

    For various cancer types, HDAC2 acts as an oncogene through the epigenetic regulation of genes and the corresponding signaling cascades in cancer development, and HDAC2 expression is gradually increases, from pre-neoplastic lesions, to low-grade dysplastic nodules, high-grade dysplastic nodules, and HCCs (Nam et al., 2005). Higher HDAC2 levels are correlated with poor survival of HCC patients (Ler et al., 2015; Quint et al., 2011), which is consistent with results of the current study. In HCC cells, inhibiting of HDAC2 disrupts the G1/S phase of the hospital settings and leads to apoptosis through upregulating the total p21, p27, and acetylated p53 levels and reducing CDK6 and BCL2 levels (Lee et al., 2014; Noh et al., 2011); these results suggest that HDAC2 could be a therapeutic target for HCC. In a murine xenograft model, systemic delivery of HDAC2 siRNA encapsulated in lipid nanoparticles reduced the growth of human HCC (Lee et al., 2014); however, this method is far from clinical use. Two small molecule inhibitors of HDACs (HDACis), SAHA (vorinostat) and FK-228 (romidepsin), have been approved by the U.S. Food and Drug Administration (FDA) to treat refractory cutaneous and peripheral T cell lymphoma (West and Johnstone, 2014). In addition to these agents, >20 different HDACis have produced encouraging results for the treatment of hematological malignancies, including Hodgkin\'s lymphoma, multiple myeloma, and acute myelocytic leukemia; however, the therapeutic effects of HDACis on solid tumors have been disappointing (West and Johnstone, 2014). In addition to toxicity, the off-target actions of the HDACis may lead to treatment failure for solid tumors. Thus, inhibitors that are selective for HDAC2 should be developed, and their therapeutic effects in HCC patients need to be addressed. RAD21, a component of the cohesion complex, is essential for chromosome segregation during the metaphase-anaphase transition of mitosis (Xu et al., 2004). RAD21 is also involved in homologous recombinational repair or the error-free repair of DNA damage, which could influence the sensitivity of gastrointestinal and breast cancers to radiotherapy or chemotherapy (Xu et al., 2010; Xu et al., 2011). High levels of nuclear RAD21 staining correlate with poor disease-specific survival of colorectal cancer patients with KRAS mutations (Deb et al., 2014) and with early relapse in patients with high-grade luminal, basal, or HER2 breast cancers (Xu et al., 2011). However, the roles of RAD21 in HCC development and progression have not been determined. In the current study, we found that nuclear RAD21 was increased in HCC tissues compared with adjacent non-tumor tissues, and higher RAD21 levels were associated with shorter OS of HCC patients. In HCC cells, RAD21 knockdown hospital settings reduced cellular proliferation and down-regulated CDK1 levels, which might partially underlie the RAD21 oncogenic activities in HCCs. These results suggest that RAD21 could be a biomarker or therapeutic target for HCC patients and that the potential intervention methods need to be developed. CDK1 is a cyclin-dependent kinase that plays critical roles in the regulating of cellular mitosis. Depending on its association with cyclin A or B, it participates in the progression of the G1/S and G2/M phases of the cell cycle through the phosphorylation of various substrates, including Ajuba (Chen et al., 2016), CDP/Cux (Santaguida et al., 2001), Bcl2 (Vantieghem et al., 2002), and Wee1 (Harvey et al., 2005) (Petrone et al., 2016). Quantitative phosphoproteomics has identified >500 candidate substrates for CDK1; these substrates are associated with genes that are G2 and M phase-specific (Petrone et al., 2016). In addition to its roles in mitosis, CDK1 also participates in the regulation of self-renewal, differentiation, and somatic reprogramming of human embryonic stem cells (Wang et al., 2017). CDK1 also stimulates the enzymatic activity of SIRT3, which enhances mitochondrial function and tumor radioresistance (Liu et al., 2015). Hyperactivation of CDK1 is associated with poor prognosis for patients with lung adenocarcinoma (Shi et al., 2016), ovarian cancer (Yang et al., 2016), renal cell carcinoma(Hongo et al., 2014), and breast cancer (Pavlou et al., 2014). For lymphomas, hepatoblastomas, and breast cancers, the inhibition of CDK1 downregulates survivin expression and induces MYC-dependent apoptosis (Goga et al., 2007; Kang et al., 2014). In the current study, we found that CDK1 was detectable in HCC cells but not in normal liver tissues and that high CDK1 independently correlated with short OS. Considering its biological roles, CDK1 expression in HCC cells might reflect proliferation status and cancer stem cell properties, which are associated with the OS of HCC patients (Fig. 1b and d). As determined with cultured cells, CDK1 knockdown or inhibition correlated with reduced cellular proliferation, suggesting that CDK1 is a therapeutic target for HCC. Various inhibitors of CDK1, including flavopiridol, BMI-1026, olomoucine, staurosporine, and RO-3306 have been developed, and some have entered phase I and II clinical trials for the treatment of a variety of solid tumors and hematologic malignancies (Wang et al., 2011). For most of these inhibitors, however, their selective activity is poor; they generally inhibit CDK1, 2, 4, and 6 with equal potency (Wang et al., 2011). As shown in early clinical trials, these inhibitors often lead to high toxicity. Selective CDK1 inhibitors can exert more favorable therapeutic effects. For example, a selective CDK1 inhibitor, RO-3306, induces cell cycle arrest and apoptosis in cancer cells but has minimal effects on normal cells (Vassilev et al., 2006). In the current study, RO-3306 reduced the proliferation of cultured HCC cells. However, whether selective inhibitors for CDK1 could act as monotherapy agents or show synergistic effects with other chemotherapeutic agents needs to be addressed.