Circular RNA‑MTO1 suppresses breast cancer cell viability and reverses monastrol resistance through regulating the TRAF4/Eg5 axis

Abstract

Circular RNAs (circRNAs), a class of endogenous RNAs, have emerged as an enigmatic class of genes. However, little is known about their value in the progression and chemoresistance of cancers. The present study sought to determine the expression profiles and potential modulatory role of circRNAs on breast cancer cell viability and monastrol resistance. Monastrol-resistant cell lines were established by exposing breast cancer cells to increasing concentrations of monastrol. A human circRNA microarray was used to search for dysregulated circRNAs in monastrol-resistant cells, then circRNA‑MTO1 (hsa‑circRNA-007874) was validated as a circRNA that exhibited elevated expression levels in monastrol-resistant cells. Mechanistic investigations suggested that upregulation of circRNA‑MTO1 suppressed cell viability, promoted monastrol-induced cell cytotoxicity and reversed monastrol resistance. Subsequently, Eg5 was identified as the functional target of circRNA‑MTO1, and MTO1 inhibited Eg5 protein level but not mRNA level. By treating with protein synthesis inhibitor cycloheximide (CHX), it was revealed that MTO1 did not affect the protein stability of Eg5. RNA-pull down experiments followed by mass spectrometry revealed that MTO1 interacted with tumor necrosis factor receptor associated factor 4 (TRAF4), and sequester TRAF4 from activating Eg5 translation, thereby inhibiting the Eg5 protein level. Taken together, the data reveal a regulatory mechanism by circRNA‑MTO1 to control cell viability and monastrol resistance in breast cancer cells.

Circ‐MTO1 correlates with favorable prognosis and inhibits cell proliferation, invasion as well as miR‐17‐5p expression in prostate cancer

“…For example, a previous in vitro study reports that circ‐MTO1/miR‐17/QKI‐5 regulatory circuit suppresses lung cancer cell proliferation . Furthermore, circ‐MTO1 inhibits cancer cell viability and reverses the resistance to monastrol in breast cancer cells . In this study, we found that circ‐MTO1 was downregulated in tumor tissue compared with non‐tumor tissue, which might be resulted from that circ‐MTO1 decreased malignant cell proliferation as shown in our in vitro experiments.…”

“…19 Furthermore, circ-MTO1 inhibits cancer cell viability and reverses the resistance to monastrol in breast cancer cells. 15 In this study, we found that circ-MTO1 was downregulated in tumor tissue provide some explanation to these results. b) Circ-MTO1 might also inhibit prostate cancer progression by repressing chemoresistance, which contributed to a better treatment response and subsequent favorable survival.…”

“…In addition, we also observed that circ‐MTO1 suppressed prostate cancer cell proliferation, invasion and downregulated miR‐17‐5p expression in prostate cancer cells, which might also provide some explanation to these results. b) Circ‐MTO1 might also inhibit prostate cancer progression by repressing chemoresistance, which contributed to a better treatment response and subsequent favorable survival …”

“…Additionally, circRNAs are increasingly implicated in prostate cancer as well; however, the relevant studies are not as abundant as the studies of other cancers . Circular RNA‐mitochondrial tRNA translation optimization 1 (circ‐MTO1) is a novel circRNA that is previously reported as an anti‐tumor gene, which inhibits liver fibrosis to prevent hepatocellular carcinoma and represses progression of lung cancer and breast cancer . And circ‐MTO1 has also been reported to express in prostate cancer (http://www.circbase.org/), Based on these facts, we supposed that circ‐MTO1 might play a crucial role in prostate cancer.…”

Increased Expression of Circular RNA circ_0005230 Indicates Dismal Prognosis in Breast Cancer and Regulates Cell Proliferation and Invasion via miR-618/ CBX8 Signal Pathway

“…CircRNAs have been recognized as imperative regulators in multiple physiological/pathological processes. Although the exact roles of most circRNAs are still unclear, accumulating evidence has documented that some of them can function as oncogenic or tumor suppressive roles in human malignancies, including BC [7][8][9]. For example, Song et al revealed that silencing of circ_0007534 attenuates BC cell progression via affecting miR-593/MUC19 axis [10].…”