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.

• Authors: Bo-Wen Liu, Tian-Jiao Wang, Lei-Lei Li, Lu Zhang, Yun-Xia Liu, Jin-Yan Feng, Yue Wu, Fei-Fei Xu, Quan-Sheng Zhang, Ming-Zhu Bao, Wei-Ying Zhang, Li-Hong Ye
• Journal: Acta pharmacologica Sinica (Acta Pharmacol Sin) Vol. 40 Issue 4 Pg. 530-538 (Apr 2019) ISSN: 1745-7254 [Electronic] United States
• PMID: 29925919 (Publication Type: Journal Article)

Chemical References

• Adaptor Proteins, Signal Transducing
• Carrier Proteins
• E2F1 Transcription Factor
• LAMTOR5 protein, human
• Membrane Proteins
• Receptors, Estrogen
• Thyroid Hormones

Topics

• Adaptor Proteins, Signal Transducing (metabolism)
• Animals
• Breast Neoplasms (metabolism, pathology)
• Carrier Proteins (metabolism)
• Cell Proliferation
• Cell Survival
• E2F1 Transcription Factor (metabolism)
• Female
• Humans
• MCF-7 Cells
• Membrane Proteins (metabolism)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Receptors, Estrogen (metabolism)
• Thyroid Hormones (metabolism)
• Thyroid Hormone-Binding Proteins