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. 2020 Oct 2;21(19):7295. doi: 10.3390/ijms21197295

Figure 2.

Figure 2

Mechanisms for restoring HLA class I expression. IFN binding to IFNR triggers Jak/STAT transduction pathway. STAT1/STAT2/IRF complex translocates to the nucleus where it binds to ISRE motifs located in HLA promoter region, inducing HLA gene transcription. EGFR and MAPK down-stream pathways suppress HLA class I surface expression. EGFR inhibitors, such as nimotuzumab, cetuximab and erlotinib, BRAF inhibitors, vemurafenib and dabrafenib, and MEK inhibitor trametinib can increase expression of both HLA class I antigens and APM components. DNMT inhibitors (azacytidine and guadecitabine) and HDAC inhibitors (vorinostat, belinostat, panobinostat, OKI-179, romidepsin and tubastatin A) avoid hypermethylation of HLA promoter region and histones hypoacetylation that cause HLA genes silencing. Abbreviations: HLA, human leukocyte antigen; IFNs, interferons; IFNR, interferon receptor; IRF, IFN regulatory factor; ISRE, IFN-sensitive response element; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; DNMT, DNA methyltransferase; HDAC, histone deacetylase; APM, antigen-processing machinery.