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Oncoprotein HBXIP induces PKM2 via transcription factor E2F1 to promote cell proliferation in ER-positive breast cancer

Abstract

We have reported that hepatitis B X-interacting protein (HBXIP, also termed LAMTOR5) can act as an oncogenic transcriptional co-activator to modulate gene expression, promoting breast cancer development. Pyruvate kinase muscle isozyme M2 (PKM2), encoded by PKM gene, has emerged as a key oncoprotein in breast cancer. Yet, the regulatory mechanism of PKM2 is still unexplored. Here, we report that HBXIP can upregulate PKM2 to accelerate proliferation of estrogen receptor positive (ER+) breast cancer. Immunohistochemistry analysis using breast cancer tissue microarray uncovered a positive association between the expression of HBXIP and PKM2. We also discovered that PKM2 expression was positively related with HBXIP expression in clinical breast cancer patients by real-time PCR assay. Interestingly, in ER+ breast cancer cells, HBXIP was capable of upregulating PKM2 expression at mRNA and protein levels in a dose-dependent manner, as well as increasing the activity of PKM promoter. Mechanistically, HBXIP could stimulate PKM promoter through binding to the −779/−579 promoter region involving co-activation of E2F transcription factor 1 (E2F1). In function, cell viability, EdU, colony formation, and xenograft tumor growth assays showed that HBXIP contributed to accelerating cell proliferation through PKM2 in ER+ breast cancer. Collectively, we conclude that HBXIP induces PKM2 through transcription factor E2F1 to facilitate ER+ breast cancer cell proliferation. We provide new evidence for the mechanism of transcription regulation of PKM2 in promotion of breast cancer progression.

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Acknowledgements

This work was supported by the grants of National Basic Research Program of China (973 Program, No. 2015CB553905), National Natural Science Foundation of China (Nos. 81372186 and 31670771), the Fundamental Research Funds for the Central Universities, and Project of Prevention and Control of Key Chronic Non Infectious Diseases (No. 2016YFC1303401).

Author information

B.-w.L., T.-j.W., and L.-l.L. designed the research methods, performed the experiments, and prepared the manuscript. B.-w.L. analyzed the data. L.Z., Y.-x.L., J.-y.F., Y.W., F.-f.X., Q.-s.Z., and M.-z.B. participated in the experiments. L.-h.Y. and W.-y.Z. conceived the projects, designed, and revised the manuscript. All authors read and approved the final manuscript.

Correspondence to Wei-ying Zhang or Li-hong Ye.

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The authors declare no competing interests.

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Keywords

  • HBXIP
  • PKM2
  • E2F1
  • breast cancer
  • proliferation

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