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

Authors: Bo-wen Liu1, Tian-jiao Wang1, Lei-lei Li1, Lu Zhang1, Yun-xia Liu2, Jin-yan Feng2, Yue Wu1, Fei-fei Xu1, Quan-sheng Zhang3, Ming-zhu Bao3, Wei-ying Zhang1, Li-hong Ye1
1 Department of Biochemistry, State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin 300071, China
2 Department of Cancer Research, State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin 300071, China
3 Department of Organ Transplantation, Key Laboratory of Organ Transplantation of Tianjin, Tianjin First Central Hospital, Tianjin 300071, China
Correspondence to: Wei-ying Zhang:, Li-hong Ye:,
DOI: 10.1038/s41401-018-0015-9
Received: 31 October 2017
Accepted: 31 January 2018
Advance online: 20 June 2018


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.
Keywords: HBXIP; PKM2; E2F1; breast cancer; proliferation

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