Fig. 3

Schematic outline of crosstalk among TMEM16A, EGFR, and PD-L1 in cancer cells. TMEM16A and EGFR interlock and work as a functional complex. The downstream pathway of EGFR in relation to TMEM16A: JAK/STAT, NF-κB, and PI3K/AKT pathways function in the proliferation of cancer cells. As illustrated, the auto-phosphorylation of PI3K leads to the activation of AKT. Downstream of TMEM16A, Ca2 + -mediated activation of CAMK pathway also activates AKT and subsequently activates NF-κB pathway. In HPV infected cells, E7 protein degradates phospho-Rb, activates NF-κB pathway. Moreover, STING-TBK1-NF-κB pathway mediates immunoregulation in HPV + cancer. Both pathways, then, collaborate to NF-κB pathway. E7 protein also affected CpG island methylation, and this positively correlates with TMEM16A expression on cell epithelia. Moreover, EGF promotes TMEM16A expression in breast cancer cells through the EGFR-STAT3 pathway. STAT3 signaling in HNSCC also plays an important role in PD-L1 upregulation. The heterodimer p65/p50 is released and migrates to the nucleus where it undergoes a series of posttranslational modifications including phosphorylation, acetylation, and methylation and binds to specific κB sites and activates NF-κB target genes. In cancer cells, NF-κB activation directly induces expression of the COPS5 gene encoding CSN5, which deubiquitinates and stabilizes PD-L1 protein, suggested increase of TMEM16A-mediated PD-L1 expression may indirectly increase the effect of anti-PD-L1 inhibition, and TMEM16A-mediated driven EGFR pathway may also increase the effect of anti-EGFR inhibitor. Combination therapy using TMEM16A and PD-L1 inhibitors may be a promising strategy to improve the survival rate of head and neck cancer patients especially when tumor gains resistance to anti-EGFR inhibitor treatment. Inhibitory/negative signals are indicated with inhibitory red arrows; Stimulatory/positive signals are indicated with green arrows