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BRCA2 And CDKN1A Interacting Protein (BCCIP) is initially identified as a tumor suppressor. Some recent studies confirmed its p53 binding capability. In this study, we explored the regulatory effect of BCCIPβ on p53 stability in HPV-positive and HPV-negative HNSCC cells. RNA-seq data from TCGA-HNSC were extracted for transcript isoform analysis in HPV-positive and HPV-negative tumors. HPV16-positive UM-SCC-47 (SCC47) and UM-SCC-104 (SCC104) and HPV-negative SCC-9 (SCC9) and UM-SCC-1 (SCC1) cell lines were used as in vitro cell models. Results showed that BCCIP β was the dominant transcript in both HPV-positive and HPV-negative HNSCC cases. Knockdown of BCCIP β decreased p53 protein concentration in the two HPV-negative cell lines but increased p53 concentration in the two HPV-positive cell lines. BCCIPβ inhibition increased proliferation and G1/S transition of SCC9 and SCC1 cells. In comparison, BCCIPβ inhibition slowed proliferation and increased G1 arrest of SCC104 and SCC47 cells. BCCIPβ inhibition prolonged the half-life of p53 protein and reduced p53 ubiquitination in the two HPV16-positive cell lines. Co-IP assay confirmed interactions among BCCIPβ, HPV E6, and p53 in both SCC104 and SCC47 cells. In comparison, only the interaction between BCCIPα and p53 was confirmed in these two cell lines. Either E6 or BCCIPβ inhibition reduced p53 ubiquitination and increased p53 concentration. However, inhibiting E6 and BCCIPβ at the same did not generate synergistic effects. On the contrary, p53 ubiquitination level was even higher in the combination group, with lower p53 concentration compared to the shE6 group. BCCIPβ overexpression in SCC47 cells with HPV E6 depletion significantly reduced p53 ubiquitination. In conclusion, this study found a novel interaction between HPV E6 and BCCIPβ in HPV16-positive HNSCC cells. The presence of HPV E6 turned BCCIPβ from a p53 stabilizer to a ubiquitination facilitator. This mechanism helps explain why BCCIPβ acted as a tumor suppressor in HPV-negative HNSCC but exerted oncogenic function in HPV16-positive HNSCC. • BCCIP β is the dominant isoform in both HPV-positive/HPV-negative HNSCC. • BCCIPβ has reverse correlations with p53 concertation in HNSCC by HPV status. • BCCIPβ has distinct regulations in proliferation of HNSCC cells by HPV status. • BCCIPβ participates in p53 ubiquitination in HPV-positive HNSCC. • BCCIPβ interacts with E6 and facilitates p53 ubiquitination in HPV-positive HNSCC. [ABSTRACT FROM AUTHOR]