||Inhibition of the HDAC/Suv39/G9a pathway restores the expression of DNA damage-dependent major histocompatibility complex class I-related chain A and B in cancer cells
Nakajima, Nakako ,
Niimi, Atsuko ,
Isono, Mayu ,
Oike, Takehiro ,
Sato, Hiro ,
Nakano, TakeshiShibata, Atsushi
Immunotherapy is expected to be the most promising in next generation cancer therapy. Immunoreceptors are often activated constitutively in cancer cells, however, such level of ligand expression is not effectively recognized by native immune system due to the tumor microenvironmental adaptation. Studies have demonstrated that NKG2D (natural-killer group 2, member D), a major activating immunoreceptor, responds to DNA damage. The upregulation of MICA/B, members of NKG2D ligands, expression after DNA damage is associated with NK cell mediated killing of cancer cells. However, the regulation of DNA damage-induced MICA/B expression is not fully elucidated in the context of type of cancer cell lines. Here, we found that MICA/B expression was various between cancer cell lines after DNA damage. Screen in terms of chromatin remodeling identified that inhibitors, related to chromatin relaxation via post-translational modification on histone H3K9, i.e. HDAC, Suv39 or G9a inhibition, restores DNA damage-dependent MICA/B expression in insensitive cells. In addition, we showed that the restored MICA/B expression was dependent on ATR as well as E2F1, a transcription factor. We further showed that low dose treatment of a HDAC inhibitor was sufficient to restore MICA/B expression in insensitive cells. Finally, we showed that HDAC inhibition restored DNA damage-dependent cytotoxic NK activity against insensitive cells. Thus, our study suggests that DNA damage-dependent MICA/B expression in insensitive cancer cells can be restored by chromatin relaxation via HDAC/Suv39/G9a pathway. Taken together, manipulation of chromatin status by therapeutic cancer drugs may potentiate the efficacy by enhancing immune activation following radiotherapy and DNA damage-associated chemotherapy.