Abstract
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.
Highlights
The oncoprotein hepatitis B X-interacting protein (HBXIP) acts as a coactivator of transcription factor in cancer
Our recent reports posit that HBXIP acts as a novel coactivator of transcription factors in the nucleus to promote proliferation and migration in breast cancer cells
HBXIP was mainly localized in the cytoplasm in the majority of breast cancer cells in clinical breast cancer tissues by immunohistochemistry staining, there were some in the
Summary
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. 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. Our data uncover that nuclear import of HBXIP requires collaboration with c-Fos, and is dependent on interacting with c-Fos and phosphorylation of both HBXIP and c-Fos in breast cancer cells. The nuclear import of HBXIP contributes to its nuclear function This finding provides new insights into the mechanism by which HBXIP imports into the nucleus in breast cancer cells
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