Cancers of the Digestive System

Elevated levels of several HDAC family members have been reported in PDAC. Immunohistochemical analysis has revealed the presence of HDAC1 in 56% of tumor samples analyzed (Miyake et al. 2008). In addition, coexpression of HDAC1 and HIF-1a has been shown to correlate with poor prognosis (Miyake et al. 2008). Moreover, HDAC2 overexpression has been identified in a tissue microarray of pancreatic cancer (Fritsche et al. 2009), which has been linked to c-Myc (Marshall et al. 2010). Importantly, it has been shown that HDAC2 mediates the resistance of PDAC cells to the chemotherapeutic drug etoposide due to silencing of the proapoptotic NOXA gene (Fritsche et al. 2009). Furthermore, increased expression of HDAC7 has been reported in pancreatic cancer (Ouaissi et al. 2008).

Elevated expression of two members of class I HDAC family has been demonstrated for gastric cancer. Increased levels of HDAC1 mRNA have been correlated to reduced expression of gelsolin and retinoic acid receptor p in primary human tumor samples (Kim et al. 2004). Moreover, increased expression of HDAC2 has been observed in advanced stages of gastric cancer (Song et al. 2005).

In a considerable subset of colorectal carcinomas, high expression of class I HDACs has been observed, which correlates with reduced patient survival (Weichert et al. 2008b); however, the contribution of different HDAC family members towards a malignant phenotype seems to be unequal. In the HCT-166 cell line, siRNA-mediated depletion of HDAC1,2, and 3 resulted in reduction of cell growth with the greatest effect seen for HDAC3 (Wilson et al. 2006). In contrast, in CX-2 cells the strongest growth inhibition was observed upon HDAC2 depletion (Weichert et al. 2008b). Interestingly, in the HT-29 colon carcinoma cell line, which is deficient in the tumor suppressor adenomatosis polyposis coli (APC), c-Myc induces HDAC2 expression (Zhu et al. 2004). Moreover, HDAC2 alone has been shown to be sufficient to prevent apoptosis of colon cancer cells, indicating a crucial role of this HDAC family member in colorectal tumorigenesis (Zhu et al. 2004).

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