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.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $57.00 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Vargo-Gogola T, Rosen JM. Modelling breast cancer: one size does not fit all. Nat Rev Cancer. 2007;7:659–72.
Bhatt S, Stender JD, Joshi S, Wu G, Katzenellenbogen BS. OCT-4: a novel estrogen receptor-alpha collaborator that promotes tamoxifen resistance in breast cancer cells. Oncogene. 2016;35:5722–34.
Melegari M, Scaglioni PP, Wands JR. Cloning and characterization of a novel hepatitis B virus x binding protein that inhibits viral replication. J Virol 1998;72:1737–43.
Bar-Peled L, Schweitzer LD, Zoncu R, Sabatini DM. Ragulator is a GEF for the rag GTPases that signal amino acid levels to mTORC1. Cell. 2012;150:1196–208.
Liu S, Li L, Zhang Y, Zhang Y, Zhao Y, You X, et al. The oncoprotein HBXIP uses two pathways to up-regulate S100A4 in promotion of growth and migration of breast cancer cells. J Biol Chem. 2012;287:30228–39.
Shi H, Li Y, Feng G, Li L, Fang R, Wang Z, et al. The oncoprotein HBXIP up-regulates FGF4 through activating transcriptional factor Sp1 to promote the migration of breast cancer cells. Biochem Biophys Res Commun. 2016;471:89–94.
Liu F, Zhang W, You X, Liu Y, Li Y, Wang Z, et al. The oncoprotein HBXIP promotes glucose metabolism reprogram-ming via downregulating SCO2 and PDHA1 in breast cancer. Oncotarget. 2015;6:27199–213.
Marusawa H, Matsuzawa S, Welsh K, Zou H, Armstrong R, Tamm I, et al. HBXIP functions as a cofactor of survivin in apoptosis suppression. EMBO J. 2003;22:2729–40.
Harris I, McCracken S, Mak TW. PKM2: a gatekeeper between growth and survival. Cell Res. 2012;22:447–9.
Sun Q, Chen X, Ma J, Peng H, Wang F, Zha X, et al. Mammalian target of rapamycin up-regulation of pyruvate kinase isoenzyme type M2 is critical for aerobic glycolysis and tumor growth. Proc Natl Acad Sci USA. 2011;108:4129–34.
Xu Q, Liu LZ, Yin Y, He J, Li Q, Qian X, et al. Regulatory circuit of PKM2/NF-kappaB/miR-148a/152-modulated tumor angiogenesis and cancer progression. Oncogene. 2015;34:5482–93.
Dong G, Mao Q, Xia W, Xu Y, Wang J, Xu L, et al. PKM2 and cancer: the function of PKM2 beyond glycolysis. Oncol Lett. 2016;11:1980–6.
Lin Y, Lv F, Liu F, Guo X, Fan Y, Gu F, et al. High expression of pyruvate kinase M2 is associated with chemosensitivity to epirubicin and 5-fluorouracil in breast cancer. J Cancer. 2015;6:1130–9.
Luo W, Hu H, Chang R, Zhong J, Knabel M, O’Meally R, et al. Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell. 2011;145:732–44.
Luo W, Semenza GL. Pyruvate kinase M2 regulates glucose metabolism by functioning as a coactivator for hypoxia-inducible factor 1 in cancer cells. Oncotarget. 2011;2:551–6.
Gao X, Wang H, Yang JJ, Liu X, Liu ZR. Pyruvate kinase M2 regulates gene transcription by acting as a protein kinase. Mol Cell. 2012;45:598–609.
Hu N, Zhang J, Cui W, Kong G, Zhang S, Yue L, et al. miR-520b regulates migration of breast cancer cells by targeting hepatitis B X-interacting protein and interleukin-8. J Biol Chem. 2011;286:13714–22.
Yu T, Cao R, Li S, Fu M, Ren L, Chen W, et al. MiR-130b plays an oncogenic role by repressing PTEN expression in esophageal squamous cell carcinoma cells. BMC Cancer. 2015;15:29.
Li L, Fang R, Liu B, Shi H, Wang Y, Zhang W, et al. Deacetylation of tumor-suppressor MST1 in Hippo pathway induces its degradation through HBXIP-elevated HDAC6 in promotion of breast cancer growth. Oncogene. 2016;35:4048–57.
Li Y, Wang Z, Shi H, Li H, Li L, Fang R, et al. HBXIP and LSD1 scaffolded by lncRNA hotair mediate transcriptional activation by c-Myc. Cancer Res. 2016;76:293–304.
Zhao Y, Li H, Zhang Y, Li L, Fang R, Li Y, et al. Oncoprotein HBXIP modulates abnormal lipid metabolism and growth of breast cancer cells by activating the LXRs/SREBP-1c/FAS signaling cascade. Cancer Res. 2016;76:4696–707.
Xu F, You X, Liu F, Shen X, Yao Y, Ye L, et al. The oncoprotein HBXIP up-regulates Skp2 via activating transcription factor E2F1 to promote proliferation of breast cancer cells. Cancer Lett. 2013;333:124–32.
Lv L, Xu YP, Zhao D, Li FL, Wang W, Sasaki N, et al. Mitogenic and oncogenic stimulation of K433 acetylation promotes PKM2 protein kinase activity and nuclear localization. Mol Cell. 2013;52:340–52.
Wang Y, Cui M, Cai X, Sun B, Liu F, Zhang X, et al. The oncoprotein HBXIP up-regulates SCG3 through modulating E2F1 and miR-509-3p in hepatoma cells. Cancer Lett. 2014;352:169–78.
Wang Y, Cai X, Zhang S, Cui M, Liu F, Sun B, et al. HBXIP up-regulates ACSL1 through activating transcriptional factor Sp1 in breast cancer. Biochem Biophys Res Commun. Commun. 2017;484:565–71.
Alves-Filho JC, Palsson-McDermott EM. Pyruvate kinase M2: a potential target for regulating inflammation. Front Immunol. 2016;7:145.
Dai H, van’t Veer L, Lamb J, He YD, Mao M, Fine BM, et al. A cell proliferation signature is a marker ofextremely poor outcome in a subpopulation of breast cancer patients. Cancer Res. 2005;65:4059–66.
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).
The authors declare no competing interests.
About this article
Effect of a Neoflavonoid (Dalbergin) on T47D Breast Cancer Cell Line and mRNA Levels of p53, Bcl-2, and STAT3 Genes
Iranian Red Crescent Medical Journal (2019)
NAMPT regulates PKM2 nuclear location through 14‐3‐3ζ: Conferring resistance to tamoxifen in breast cancer
Journal of Cellular Physiology (2019)
Molecular Therapy (2019)