The Nuclear Import of Oncoprotein Hepatitis B X-interacting Protein Depends on Interacting with c-Fos and Phosphorylation of Both Proteins in Breast Cancer Cells

Aberrant nuclear localization of oncogenic transcription factors and coactivators always leads to the development of cancer. We have reported that the oncoprotein hepatitis B X-interacting protein (HBXIP) acts as a novel transcriptional coactivator to promote proliferation and migration of breast cancer cells. However, the mechanism of regulating the nuclear import of HBXIP remains unclear. In the present study, we found that HBXIP interacted with c-Fos through their leucine zipper domains in vitro and in vivo . Interestingly, the leucine zipper mutant of HBXIP (or c-Fos) was unavailable to bind to c-Fos (or HBXIP), resulting in the disappearance of nuclear localization of HBXIP. Moreover, we revealed that the nuclear import of HBXIP was required for phosphorylation of c-Fos at Thr 232 , Thr 325 , Thr 331 , and Ser 374 by ERK1/2. In addition, the mutant of HBXIP at the Ser 108 phosphorylation site failed to import into the nucleus. Strikingly, we found that the kinase ataxia telangiectasia mutated (ATM) phosphorylated HBXIP at Ser 108 . The knockdown of ATM by siRNA remarkably decreased the levels of serine phosphorylation and blocked the nuclear import of HBXIP. Then, we identified that ATM could bind to HBXIP. Moreover, we validated that the nuclear import of HBXIP contributed to its nuclear function. Therefore, we conclude that the nuclear import of the oncoprotein HBXIP requires interaction with c-Fos through their leucine zipper domains and phosphorylation of both proteins in breast cancer cells. Thus, our findings provide new insights into the mechanism of the nuclear import of HBXIP. Therapeutically, the block of the nuclear import of HBXIP is significant in breast cancer. Background: The oncoprotein HBXIP acts as a coactivator of transcription factor in cancer. Results: The nuclear import of HBXIP depends on interacting with c-Fos and ATM-mediated phosphorylation of HBXIP and p-ERK1/2-mediated phosphorylation of c-Fos. Conclusion: The nuclear import of HBXIP is required for collaboration with c-Fos. Significance: We provide new insights into the mechanism that HBXIP imports into the nucleus in breast cancer cells.