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.

中文翻译：

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癌蛋白 HBXIP 通过转录因子 E2F1 诱导 PKM2，促进 ER 阳性乳腺癌细胞增殖。


我们报道了乙型肝炎 X 相互作用蛋白（HBXIP，也称为 LAMTOR5）可以作为致癌转录共激活因子来调节基因表达，促进乳腺癌的发展。由 PKM 基因编码的丙酮酸激酶肌肉同工酶 M2 (PKM2) 已成为乳腺癌中的关键癌蛋白。然而，PKM2的调控机制仍未被探索。在此，我们报告 HBXIP 可以上调 PKM2，加速雌激素受体阳性 (ER+) 乳腺癌的增殖。使用乳腺癌组织微阵列进行的免疫组织化学分析发现 HBXIP 和 PKM2 的表达之间呈正相关。我们还通过实时PCR检测发现临床乳腺癌患者中PKM2的表达与HBXIP的表达呈正相关。有趣的是，在 ER+ 乳腺癌细胞中，HBXIP 能够以剂量依赖的方式上调 PKM2 mRNA 和蛋白质水平的表达，并增加 PKM 启动子的活性。从机制上讲，HBXIP 可以通过与 -779/-579 启动子区域结合来刺激 PKM 启动子，从而共同激活 E2F 转录因子 1 (E2F1)。在功能、细胞活力、EdU、集落形成和异种移植肿瘤生长测定中，HBXIP 有助于通过 PKM2 加速 ER+ 乳腺癌中的细胞增殖。总的来说，我们得出结论，HBXIP 通过转录因子 E2F1 诱导 PKM2 促进 ER+ 乳腺癌细胞增殖。我们为 PKM2 转录调控促进乳腺癌进展的机制提供了新的证据。