Journal
CANCER LETTERS
Volume 521, Issue -, Pages 196-209Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2021.09.001
Keywords
microRNAs; Histone deacetylase inhibitors; Cell growth; Transcription
Categories
Funding
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University
- National Natural Science Foundation of China [81772964, 81974448, 82073066]
- National Major New Drug Creation Science and Technology Major Special Fund Funding Project [2020ZX09201017]
- Science and Technology Planning Project of Guangdong Province [2017B020209003]
- Guangdong Medical Research Foundation [B2019126]
- Shenzhen Science and Technology Innovation Commission [JCYJ20180306170328854]
- President Foundation of Nanfang Hospital, Southern Medical University [2020C005]
- Department of Gastroenterology, Longgang District People's Hospital, Shenzhen
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miR-769-5p/miR-769-3p acts as a tumor suppressor in gastric cancer by targeting IGF1R and through the STAT3-IGF1R-HDAC3 complex. Treatment with the HDAC inhibitor SAHA triggers the expression of miR-769-5p/miR-769-3p, leading to inhibition of proliferation and induction of apoptosis in gastric cancer cells.
Previous reports have shown that histone deacetylase inhibitors (HDACi) can alter miRNA expression in a range of cancers. Both the 5p-arm and 3p-arm of mature miRNAs can be expressed from the same precursor and involved in cancer progress. Nevertheless, the detailed mechanism by which vorinostat (SAHA), a HDACi, triggers miR-769-5p/miR-769-3p-mediated suppression of proliferation and induces apoptosis in gastric cancer (GC) cells remains elusive. Here, we showed that the miRNA-seq analysis of GC cells treated with SAHA identified seven differentially expressed miRNAs with both strands of the miRNA duplex. miR-769-5p/miR-769-3p expression was downregulated in GC tissues compared with normal tissues. Functionally, high expression of miR769-5p/miR-769-3p blocked the malignant abilities of GC cells. Mechanistically, miR-769-5p/miR-769-3p targeted IGF1R and IGF1R overexpression rescued the effects of miR-769-5p/miR-769-3p on GC cells growth and metastasis. Moreover, STAT3 bound to the promoter of miR-769. Furthermore, miR-769-5p/miR-769-3p expression was negatively regulated by the STAT3-IGF1R-HDAC3 complex. Besides, miR-769-5p/miR-769-3p synergized with SAHA to promote GC cells apoptosis. Our studies suggest that miR-769-5p/miR-769-3p acts as a tumor suppressor by the STAT3-IGF1R-HDAC3 complex. Moreover, SAHA triggers miR-769-5p/miR-769-3pmediated inhibition of proliferation and induces apoptosis in GC cells.
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