Adenylate Kinase 4 Modulates the Resistance of Breast Cancer Cells to Tamoxifen through an m6A-Based Epitranscriptomic Mechanism

Liu, Xiaochuan; Gonzalez, Gwendolyn Michelle; Dai, Xiaoxia; Miao, Weili; Yuan, Jun; Huang, Ming Shyan; Bade, David; Lin, Li; Sun, Yuxiang; Wang, Yinsheng

doi:10.1016/j.ymthe.2020.09.007

Cited by 68 publications

(66 citation statements)

References 48 publications

(70 reference statements)

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“…Therapeutic resistance of breast cancer was also dependent on the m 6 A-based epitranscriptomic mechanism. Adriamycin resistance derived from METTL3 induced the maturation of pri-miRNA-221-3p [ 105 ], while tamoxifen resistance arose from METTL3-mediated overexpression of adenylate kinase 4 (AK4) [ 106 ]. Conversely, poor prognosis of the triple-negative breast cancer (TNBC) was associated with lower expression of METTL3, suggesting the tumor suppressing role of METTL3 [ 107 ].…”

Section: Mettl3 Mediates Tumorigenesis Via Rna Methylationmentioning

confidence: 99%

Novel insights into the m6A-RNA methyltransferase METTL3 in cancer

et al. 2021

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N6-methyladenosine (m6A) is a prevalent internal RNA modification in higher eukaryotic cells. As the pivotal m6A regulator, RNA methyltransferase-like 3 (METTL3) is responsible for methyl group transfer in the progression of m6A modification. This epigenetic regulation contributes to the structure and functional regulation of RNA and further promotes tumorigenesis and tumor progression. Accumulating evidence has illustrated the pivotal roles of METTL3 in a variety of human cancers. Here, we systemically summarize the interaction between METTL3 and RNAs, and illustrate the multiple functions of METTL3 in human cancer. METLL3 is aberrantly expressed in a variety of tumors. Elevation of METTL3 is usually associated with rapid progression and poor prognosis of tumors. On the other hand, METTL3 may also function as a tumor suppressor in several cancers. Based on the tumor-promoting effect of METTL3, the possibility of applying METTL3 inhibitors is further discussed, which is expected to provide novel insights into antitumor therapy.

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Section: Mettl3 Mediates Tumorigenesis Via Rna Methylationmentioning

confidence: 99%

Novel insights into the m6A-RNA methyltransferase METTL3 in cancer

et al. 2021

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“…and demethylase enzymes (ALKBH5 and FTO) 17 . Previous studies showed these proteins played important roles in breast cancer developments 18 - 22 , especially METTL3, which is the key component in methyltransferase enzymes 20 , 23 - 25 . For example, METTL3 could promote breast cancer progression via inhibiting tumor suppressor let-7g or targeting Bcl-2 20 , 25 , though another study showed METTL3 inhibited metastasis of triple-negative breast cancer by decreasing COL3A1 24 .…”

Section: Introductionmentioning

confidence: 99%

“…For example, METTL3 could promote breast cancer progression via inhibiting tumor suppressor let-7g or targeting Bcl-2 20 , 25 , though another study showed METTL3 inhibited metastasis of triple-negative breast cancer by decreasing COL3A1 24 . METTL3 also increased adenylate kinase 4 expression, causing the resistance of breast cancer cells to tamoxifen 23 . A recent interesting study displayed circ_KIAA1429 derived from KIAA1429 , a part of methyltransferase complex, could accelerate hepatocellular carcinoma advancement through the mechanism of m6A-YTHDF3-Zeb1 26 .…”

Section: Introductionmentioning

confidence: 99%

CircMETTL3, upregulated in a m6A-dependent manner, promotes breast cancer progression

Yang

Dai

et al. 2021

Int. J. Biol. Sci.

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Growing evidence indicates N6-methyladenosine (m6A) has biological function in oncogenesis. METTL3, the catalytic component, is the most important part of methyltransferase complex and plays a crucial role in cancers. However, the biological function of circRNAs derived from METTL3 in breast cancer and the underlying molecular mechanism remains unclear. Herein, we report circMETTL3, which has not been explored in breast cancer, and it is markedly upregulated in breast cancer. Moreover, we uncovered that circMETTL3 could facilitate cell proliferation, migration and invasion in breast cancer. Mechanism investigation showed that circMETTL3 might act as a competing endogenous RNA (ceRNA) of miR-31-5p and upregulate its target cyclin-dependent kinases (CDK1). Moreover, m6A modification of circMETTL3 might affect its expression. Taken together, our results elucidate that circMETTL3 promotes breast cancer progression through circMETTL3/miR-31-5p/CDK1 axis. Moreover, METTL3, the host gene of circMETTL3, may regulate circMETTL3 expression in an m6A-dependent manner, while circMETTL3 has no effect on METTL3 expression, providing a new relationship between the circRNA and the corresponding host gene. Thus, it may serve as a new therapeutic target for breast cancer.

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“…m6A modi cation is a dynamic process, controlled by methyltransferase enzymes (including METTL3, METTL14, WTAP, KIAA1429 et al) and demethylase enzymes (ALKBH5 and FTO) [17]. Previous studies showed these proteins played important roles in breast cancer developments [18][19][20][21][22], especially METTL3, which is the key component in methyltransferase enzymes [20,[23][24][25]. For example, METTL3 could promote breast cancer progression via inhibiting tumor suppressor let-7 g or targeting Bcl-2 [20,25], though another study showed METTL3 inhibited metastasis of triple-negative breast cancer by decreasing COL3A1 [24].…”

mentioning

confidence: 99%

“…For example, METTL3 could promote breast cancer progression via inhibiting tumor suppressor let-7 g or targeting Bcl-2 [20,25], though another study showed METTL3 inhibited metastasis of triple-negative breast cancer by decreasing COL3A1 [24]. METTL3 also increased adenylate kinase 4 expression, causing the resistance of breast cancer cells to tamoxifen [23]. A recent interesting study displayed circ_KIAA1429 derived from KIAA1429, a part of methyltransferase complex, could accelerated hepatocellular carcinoma advancement through the mechanism of m6A-YTHDF3-Zeb1 [26].…”

mentioning

confidence: 99%

CircMETTL3, Upregulated in a m6A-dependent Manner, Promotes Breast Cancer Progression through circMETTL3/miR-31-5p/CDK1 axis

Yang

Dai

et al. 2020

Preprint

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Background: Growing evidence indicates N6-methyladenosine (m6A) has biological function in oncogenesis. METTL3, the catalytic component, is the most important part of methyltransferase complex and plays a crucial role in cancers. However, the biological function of circRNAs derived from METTL3 and the underlying molecular mechanism remains unclear.Methods: Quantitative real-time PCR was used to determine the circMETTL3 expression in breast cancer tissues and cell lines. Then, functional experiments in vitro and in vivo were performed to investigate the effects of circMETTL3 on tumor growth and metastasis in breast cancer. Mechanistically, fluorescent in situ hybridization, dual luciferase reporter assay, RNA pull-down and RNA immunoprecipitation experiments were performed to confirm the interaction between circMETTL3 and miR-31-5p in breast cancer. Furthermore, we explored regulatory effects of m6A modification on circMETTL3 expression with m6A RNA immunoprecipitation.Results: We found that circMETTL3 was significantly upregulated in breast cancer. The results indicated that circMETTL3 could promote breast cancer cell proliferation, migration and invasion as well as tumorigenesis in vivo. Mechanistic analysis showed that circMETTL3 might act as a ceRNA (competing endogenous RNA) of miR-31-5p to relieve the repressive effect of miR-31-5p on its target cyclin-dependent kinases (CDK1). Moreover, m6A modification of circMETTL3 might affect its expression.Conclusion: Our findings suggest that circMETTL3 promotes breast cancer progression through circMETTL3/miR-31-5p/CDK1 axis. Moreover, METTL3, the host gene of circMETTL3, may regulates circMETTL3 expression in a m6A-dependent manner, while circMETTL3 has no effect on METTL3 expression, providing a new relationship between the circRNA and the corresponding host gene. Thus, it may serve as a new diagnostic marker or therapeutic target for breast cancer patients.

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Adenylate Kinase 4 Modulates the Resistance of Breast Cancer Cells to Tamoxifen through an m6A-Based Epitranscriptomic Mechanism

Cited by 68 publications

References 48 publications

Novel insights into the m6A-RNA methyltransferase METTL3 in cancer

Novel insights into the m6A-RNA methyltransferase METTL3 in cancer

CircMETTL3, upregulated in a m6A-dependent manner, promotes breast cancer progression

CircMETTL3, Upregulated in a m6A-dependent Manner, Promotes Breast Cancer Progression through circMETTL3/miR-31-5p/CDK1 axis

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Adenylate Kinase 4 Modulates the Resistance of Breast Cancer Cells to Tamoxifen through an m6A-Based Epitranscriptomic Mechanism

Cited by 68 publications

References 48 publications

Novel insights into the m6A-RNA methyltransferase METTL3 in cancer

Novel insights into the m6A-RNA methyltransferase METTL3 in cancer

CircMETTL3, upregulated in a m6A-dependent manner, promotes breast cancer progression

CircMETTL3, Upregulated in a m6A-dependent Manner, Promotes Breast Cancer Progression through&nbsp;circMETTL3/miR-31-5p/CDK1 axis

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CircMETTL3, Upregulated in a m6A-dependent Manner, Promotes Breast Cancer Progression through circMETTL3/miR-31-5p/CDK1 axis