Figure 2: Mechanisms Regulating HLA Class-I Antigen Processing Machinery Component Expression in Cancer Cells.

HLA class-I APM components are involved in the synthesis and expression of HLA class-I trimolecular complexes. Their expression is regulated by transcription factors IRF1 and NF-κB, as well as enhanceosome transactivator NLRC5. Overexpression and/or activation of histone deacetylases, DNA methyltransferases, and polycomb repressive complex 2 (PRC2) enzymatic component EZH2 may reduce DNA accessibility of HLA class-I APM component promoter/enhancer regions, preventing transcription factors from binding. Activating mutations or amplifications in the receptor tyrosine kinase/MAPK signaling pathway may inactivate STAT1, downregulating IRF1, NLRC5, and HLA class-I APM component expression. MAPK activation may also inactivate STAT3, leading to HLA class-I APM component downregulation. Type I and type II interferons upregulate HLA class-I APM component expression through JAK/STAT1 activation. cGAS, a cytoplasmic DNA sensor that activates stimulator of interferon genes (STING) and downstream TBK1/IKKε, may also induce HLA class-I APM component transcription. IRF3/IRF7-dependent type I interferon secretion represents one of the underlying mechanisms. The other mechanism is canonical NF-κB activation. The latter is also induced by tumor necrosis factor α (TNFα) and Toll-like receptor (TLR)/interleukin-1 receptor (IL-1R) agonists. Non-canonical NF-κB activation mediated by binding of ligands to TNF receptor superfamily members can also induce HLA class-I APM component transcription. Post-translationally, autophagy receptor NBR1 mediates HLA class-I trimolecular complex degradation via the autophagy-lysosomal pathway, while secreted enzyme PCSK9 mediates degradation of HLA class-I trimolecular complexes via the endosomal-lysosomal pathway.