METTL3 regulates WTAP protein homeostasis

Abstract

The Wilms tumor 1 (WT1)-associated protein (WTAP) is upregulated in many tumors, including, acute myeloid leukemia (AML), where it plays an oncogenic role by interacting with different proteins involved in RNA processing and cell proliferation. In addition, WTAP is also a regulator of the nuclear complex required for the deposition of N6-methyladenosine (m6A) into mRNAs, containing the METTL3 methyltransferase. However, it is not clear if WTAP may have m6A-independent regulatory functions that might contribute to its oncogenic role. Here, we show that both knockdown and overexpression of METTL3 protein results in WTAP protein upregulation, indicating that METTL3 levels are critical for WTAP protein homeostasis. However, we show that WTAP upregulation is not sufficient to promote cell proliferation in the absence of a functional METTL3. Therein, these data indicate that the reported oncogenic function of WTAP is strictly connected to a functional m6A methylation complex.

N6-Methyladenosine Role in Acute Myeloid Leukaemia

“…Similar results were also found in lung cancer [58]. It was also demonstrated that cytoplasmic METTL3 can promote translation of specific mRNAs independently from its catalytic activity [54,58]. Moreover, higher levels of cytoplasmic METTL3 results in concomitant increase of WTAP protein expression [54].…”

MTCH2 promotes adipogenesis in intramuscular preadipocytes via an m 6 A‐YTHDF1‐dependent mechanism

“…Epigenetic imprinting through DNA methylation (7)(8)(9), microRNAs (10,11), and noncoding RNAs (12) play important roles in preadipocytes adipogenesis. N 6 -methyladenosine (m 6 A) is the most prevalent chemical modification in eukaryotic mRNA (13), and it is installed by the methyltransferase complex mainly consisting of the methyltransferase-like (METTL)3-METTL14-WTAP core, which are essential components with catalytic and structural functions, respectively (14)(15)(16). However, this process could be reversed by fat mass and obesity-associated protein (FTO) (17) or AlkBH5 (18).…”

Effect of m6A RNA Methylation Regulators on Malignant Progression and Prognosis in Renal Clear Cell Carcinoma

“…Recently, more and more studies have suggested that the abnormal expression of the m 6 A RNA methylation regulators is involved in human cancer. The writer WTAP was reported to be a oncogene in different cancers, such as AML (38), glioblastoma (39), and pancreatic ductal adenocarcinoma (40). The eraser ALKBH5 was observed to be up regulated in glioblastoma stemlike cell (GSCs), leading to the initiation and development of glioblastoma (41).…”