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Aerobic glycolysis (the Warburg effect) facilitates tumor growth, and drugs targeting aerobic glycolysis are being developed. However, how the Warburg effect is directly regulated is largely unknown. Here we show that transcription factor SIX1 directly increases the expression of many glycolytic genes, promoting the Warburg effect and tumor growth in vitro and in vivo. SIX1 regulates glycolysis through HBO1 and AIB1 histone acetyltransferases. Cancer-related SIX1 mutation increases its ability to promote aerobic glycolysis and tumor growth. SIX1 glycolytic function is directly repressed by microRNA-548a-3p, which is downregulated, inversely correlates with SIX1, and is a good predictor of prognosis in breast cancer patients. Thus, the microRNA-548a-3p/SIX1 axis strongly links aerobic glycolysis to carcinogenesis and may become a promising cancer therapeutic target.

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Dysregulation of the epidermal growth factor receptor (EGFR) promotes cancer cell growth, invasion and metastasis. However, its relevant downstream effectors are still limited. Here, we show that EGFR promotes breast tumor growth and metastasis by downregulating the tumor suppressor micoRNA-338-3p (miR-338-3p) and activating the EYA2 (EYA transcriptional coactivator and phosphatase 2) oncoprotein. EGFR represses miR-338-3p expression largely through HIF1α transcription factor. miR-338-3p inhibits EYA2 expression by binding to the 3′-untranslated region of EYA2. EGFR increases EYA2 expression via HIF1α repression of miR-338-3p. Through the miR-338-3p/EYA2 pathway, EGFR increases breast cancer cell growth, epithelial-to-mesenchymal transition, migration, invasion and lung metastasis in vitro and in a allograft tumor mouse model in vivo. In breast cancer patients, miR-338-3p expression negatively correlates with the expression of EGFR and EYA2, EGFR status positively associates with EYA2 expression, and miR-338-3p and EYA2 predict breast cancer lung metastasis when expressed in primary breast cancers. These data suggest that the miR-338-3p/ EYA2 axis contributes to EGFR-mediated tumor growth and lung metastasis and that miR-338-3p activation or EYA2 inhibition or combination therapy targeting EGFR/miR-338-3p/EYA2 axis may be a promising way to treat patients with metastatic cancer. Cell Death and Disease (2017) 8, e2928; doi:10.1038/cddis.2017.325; published online 13 July 2017The epidermal growth factor receptor (EGFR) is a member of the ErbB (avian erythroblastosis oncogene B) family of receptors and activates multiple signaling pathways, including mitogen-activated protein kinase (MAPK)/extracellular signalregulated kinases (ERK) and phosphoinositide-3-kinase (PI3K)/V-AKT murine thymoma viral oncogene homolog (AKT) pathways. 1-3 EGFR activation regulates many biological processes, such as cell proliferation, invasion, metastasis and apoptosis. [4][5][6] EGFR is overexpressed in various human cancers, including lung cancer, breast cancer, colon cancer and glioblastoma, and is associated with tumor malignancy and poor prognosis. 7-10 Thus, EGFR and its downstream signaling effectors have become targets for cancer therapy. 11 Approximately 90% of deaths associated with cancer are due to distant metastases. 12 Many cancers can metastasize anywhere in body but primarily metastasizes to some organs or tissues. For instance, lungs and bones are frequent sites of breast cancer metastasis. Although EGFR dysregulation enhances cancer metastasis, the relevant downstream effectors are largely unknown.MicroRNAs (miRNAs) are small noncoding RNA molecules (about 22 nucleotides in length), which function in RNA silencing and post-transcriptional regulation of gene expression. miRNAs participate in many biological processes, such as cell proliferation, invasion, metastasis, and apoptosis. 13 Recently, EGFR has been shown to promote prostate cancer bone metastasis by decreasing the expression of miR-1, a tumor suppressor, and inc...

ADAMTS-5 was identified as a novel direct target of miR-30a. IL-1β suppresses miR-30a expression through activation of AP-1 (c-jun/c-fos). AP-1/miR-30a is essential for IL-1β-induced ADAMTS-5 upregulation in OA. Downregulation of miR-30a in OA is negatively correlated with ADAMTS-5 expression.