Synergy between histone deacetylase inhibitors and DNA- damaging agents is mediated by histone deacetylase 2 in colorectal cancer

Previous studies have associated the overexpression of histone deacetylase 2 (HDAC2) and the presence of TP53 mutations with the progression to advanced stage drug resistant colorectal cancer (CRC). However, the mechanistic link between HDAC2 expression and the TP53 mutational status has remained unexplored. Here, we investigated the function of HDAC2 in drug resistance by assessing the synergistic effects of DNA-targeted chemotherapeutic agents and HDAC inhibitors (HDACis) on two TP53-mutated colorectal adenocarcinoma CRC cell lines (SW480 and HT-29) and on the TP53-wild type carcinoma cell line (HCT116 p53+/+) and its TP53 deficient sub-line (HCT116 p53-/-). We showed that in the untreated SW480 and HT-29 cells the steady-state level of HDAC2 was low compared to a TP53-wild type carcinoma cell line (HCT116 p53+/+). Increased expression of HDAC2 correlated with drug resistance, and depletion by shRNA sensitised the multi-drug resistance cell line HT-29 to CRC chemotherapeutic drugs such as 5-fluorouracil (5-FU) and oxaliplatin (Oxa). Combined treatment with the HDACi suberoylanilide hydroxamic acid plus 5-FU or Oxa reduced the level of HDAC2 expression, modified chromatin structure and induced mitotic cell death in HT-29 cells. Non-invasive bioluminescence imaging revealed significant reductions in xenograft tumour growth with HDAC2 expression level reduced to <50% in treated animals. Elevated levels of histone acetylation on residues H3K9, H4K12 and H4K16 were also found to be associated with resistance to VPA/Dox or SAHA/Dox treatment. Our results suggest that HDAC2 expression rather than the p53 mutation status influences the outcome of combined treatment with a HDACi and DNA-damaging agents in CRC.

Understanding citizen media as practice: agents, processes, publics

Much recent commentary on citizen media has focused on online platforms as means through which citizens may disseminate self-produced media content that challenges dominant discourses or makes visible hidden realities. This chapter goes beyond a concern with media content to explore the much broader range of socially situated practices that develop around citizen media. Drawing on Couldry’s proposal for a practice paradigm in media research, it suggests shifting the focus from ‘citizen media’ to ‘citizen media practices’ and demonstrates, through a case study of communication activism in the World Social Forum, how this framework can bring into view a broad range of citizen media practices (beyond those directly concerned with the production and circulation of media content), the different forms of agency that such practices make possible, and the social fabric they can help generate. I conclude by arguing that a practice framework necessitates a rethink of the way that the concept of (counter-) publics is used in the context of citizen media. Citizen media practices of the kind described here can be understood not only as practices of ‘making public’ previously unreported issues and perspectives, but as practices of public¬-making: practices that support the formation of publics.