miR-1273g silences MAGEA3/6 to inhibit human colorectal cancer cell growth via activation of AMPK signaling

• Published in: Cancer letters Vol. 435; pp. 1 - 9
• Main Authors: Wu, Fang, Liu, Fang, Dong, Lemei, Yang, Han, He, Xixi, Li, Lili, Zhao, Lihao, Jin, Sisi, Li, Gang
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 28.10.2018; Elsevier Limited
• Subjects: AMP; AMP-activated protein kinase; Antigen (tumor-associated); Apoptosis; Cancer therapies; Cell activation; Cell culture; Cell cycle; Cell growth; Cell proliferation; Colon cancer; Colorectal cancer; Colorectal carcinoma; CRISPR; Kinases; Melanoma; Melanoma antigen A3/A6; microRNA; MicroRNAs; miRNA; Molecularly-targeted therapy; Proteins; Tissues; Tumors; Ubiquitin; Ubiquitin-protein ligase; China; microRNA; Molecularly-targeted therapy; AMP-activated protein kinase; Melanoma antigen A3/A6
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2018.07.031

AMP-activated protein kinase (AMPK) is a metabolic regulator that acts to limit the growth of cancer cells. AMPK is downregulated by melanoma antigens A3/6 (MAGEA3/6), which are cancer-specific proteins that enhance the activity of specific E3 ubiquitin ligases to ubiquitinate and degrade AMP-activated protein kinase α1 (AMPKα1). Here, using a bioinformatic approach, we identified a microRNA, miR-1273g-3p, that is predicted to target the 3′ untranslated region (UTR) of MAGEA3/6. Analyzing miR-1273g-3p expression in human colon cancer tissues, we found a reduction in miR-1273g-3p expression correlating with increased MAGEA3/6 expression and AMPKα1 downregulation. Expression of miR-1273g in HT-29 cells and primary human colon cancer cells down-regulated MAGEA3/6, leading to AMPKα1 upregulation, inhibition of proliferation and cell apoptosis. The anti-CRC activity of miR-1273g was blocked by AMPKα1 knockout. MAGEA3/6 shRNA silencing mimicked and abolished miR-1273g-induced actions in HT-29 cells. In vivo, miR-1273g- or MAGEA3/6 shRNA-expressing HT-29 tumors grew significantly slower than control tumors. We propose a novel miRNA-based mechanism, whereby miR-1273g represses MAGEA3/6 expression in human CRC cells and tissues, which may provide a novel cancer-specific therapeutic. •miR-1273g induces MAGEA3/6 downregulation and AMPK activation in colorectal cancer cells.•miR-1273g-3p downregulation in colon cancer tissues correlates with AMPK in-activation.•miR-1273g-induced cytotoxicity in HT-29 cells is nullified by AMPKα1 knockout.•miR-1273g-expressing HT-29 tumors grew significantly slower than control tumors.