N6-methyladenosine contributes to cellular phenotype in a genetically-defined model of breast cancer progression

Abstract

The mRNA modification N6-methyladenosine (m6A) is involved in many post-transcriptional regulatory processes including mRNA stability and translational efficiency. However, it is also imperative to correlate these processes with phenotypic outputs during cancer progression. Here we report that m6A levels are significantly decreased in genetically-defined immortalized and oncogenically-transformed human mammary epithelial cells (HMECs), as compared with their primary cell predecessor. Furthermore, the m6A methyltransferase (METTL3) is decreased and the demethylase (ALKBH5) is increased in the immortalized and transformed cell lines, providing a possible mechanism for this basal change in m6A levels. Although the immortalized and transformed cells showed lower m6A levels than their primary parental cell line, overexpression of METTL3 and METTL14, or ALKBH5 knockdown to increase m6A levels in transformed cells increased proliferation and migration. Remarkably, these treatments had little effect on the immortalized cells. Together, these results suggest that m6A modification may be downregulated in immortalized cells as a brake against malignant progression. Finally, we found that m6A levels in the immortalized and transformed cells increased in response to hypoxia without corresponding changes in METTL3, METTL14 or ALKBH5 expression, suggesting a novel pathway for regulation of m6A levels under stress.

RETRACTED: METTL14 Suppresses CRC Progression via Regulating N6-Methyladenosine-Dependent Primary miR-375 Processing

“…METTL14, a key component of the m6A methyltransferase complex, has been reported to be dysregulated and play critical roles in the tumorigenesis of glioblastoma, 28 AML, 33 and breast cancer. 34 At present, the studies on the role of m6A modification in CRC remain elusive. Bai et al 35 reported that YTH m6A RNA binding protein 1 (YTHDF1) is a core factor in RNA methylation modification and plays a vital oncogenic role in CRC.…”

Contributions and prognostic values of m6A RNA methylation regulators in non‐small‐cell lung cancer

“…m 6 A modification is the most prevalent chemical modification carried by cellular RNAs. The m 6 A has been implicated in tumorigenesis, due to its capacity of regulating RNA splicing, translocation, stability, and translation (Chen et al, 2018; Chen et al, 2019; Fry et al, 2018; He et al, 2018; Ianniello & Fatica, 2018; Li et al, 2018; Liu et al, 2018; Liu et al, 2018). However, the knowledge of m 6 A modification remains preliminary in the cancer field, especially in lung cancer.…”

“…To date, this type of chemical modification of RNA has been involved in a broad spectrum of cancer types (Chen et al, 2018; Chen, Zhang, & Zhu, 2019; Fry et al, 2018; He et al, 2018; Ianniello & Fatica, 2018; Liu et al, 2018; Liu et al, 2018), especially acute myeloid leukemia (AML), glioblastoma, hepatocellular carcinoma (HCC), and breast cancer. Some studies have reported abnormal m 6 A status in lung cancer (Du et al, 2017; Lin, Choe, Du, Triboulet, & Gregory, 2016; Liu et al, 2018); however, the implications of m 6 A RNA modification regulators in NSCLC are mainly unknown.…”

Reshaping the role of m6A modification in cancer transcriptome: a review

“…Increasingly evidence showed that the levels and effects of m6A in tumor cells change continuously as the tumor progresses. For instance, changes in cellular m6A levels can alter the phenotypes of breast cancer cells [ 60 ] and the malignancy of gastric cancer [ 61 ].…”