Via further exploration, we confirmed that both DGCR8 and E6 positively regulated the expression of miR-27a-3p in HNSCC; knockdown of DGCR8 counteracted the upregulation of miR-27a-3p induced by E6 overexpression, while overexpression of DGCR8 restored the level of miR-27a-3, which was decreased by E6 knockdown, suggesting that HPV16 E6 upregulated miR-27a-3p via DGCR8. Here, DGCR8 is linked to head and neck squamous cell carcinoma.