METTL3 stabilization by PIN1 promotes breast tumorigenesis via enhanced m6A-dependent translation

Abstract

Methyltransferase-like 3 (METTL3) is the catalytic subunit of the N 6 -adenosine methyltransferase complex responsible for N 6 -methyladenosine (m 6 A) modi cation of mRNA in mammalian cells. Although METTL3 expression is increased in several cancers, the regulatory mechanisms are unclear. We explored the regulatory roles of peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1) in METTL3 stability and m6A modi cation of mRNA. PIN1 interacted with METTL3 and prevented its ubiquitin-dependent proteasomal and lysosomal degradation. It stabilized METTL3, which increased the m6A modi cation of transcriptional coactivator with PDZ-binding motif (TAZ) and epidermal growth factor receptor (EGFR) mRNA, resulting in their e cient translation. PIN1 knockout reduced polysome assembly and TAZ and EGFR mRNA in polysome fractions. Inhibition of MEK1/2 kinases and PIN1 destabilized METTL3, which impeded breast cancer cell proliferation and induced cell cycle arrest at the G0/G1 phases. METTL3 knockout reduced PIN1 overexpression-induced colony formation in MCF7 cells and enhanced tumor growth in 4T1 cells in an orthotopic mouse model. In clinical settings, METTL3 expression signi cantly increased with tumor progression and was positively correlated with PIN1 expression in breast cancer tissues. Thus, PIN1 plays a regulatory role in mRNA translation, and the PIN1/METTL3 axis may be an alternative therapeutic target in breast cancer.

METTL3 as a master regulator of translation in cancer: mechanisms and implications

“…In breast cancer cells, peptidyl-prolyl cis- trans isomerase NIMA-interacting 1 (PIN1) interacts with METTL3 and prevents its ubiquitin-dependent proteasomal and lysosomal degradation. Specifically, PIN1-stabilized METTL3 is able to promote m 6 A-mediated translation of the transcriptional coactivator with PDZ-binding motif ( TAZ ) and EGFR , affecting cell proliferation and cell cycle ( 100 ). Furthermore, METTL3-mediated m 6 A-modification promotes CDCP1 translation in gastric and bladder cancers ( 101 ).…”

Regulation of m6A Methylome in Cancer: Mechanisms, Implications, and Therapeutic Strategies

“…The stability of METTL3 phosphorylated at S525 is regulated by the prolyl cis/trans isomerase PIN1. The peptidyl-prolyl isomerase (PPIase) domain of PIN1 interacts with METTL3 and promotes its stability by preventing proteasomal and lysosomal degradation in breast cancer cells [ 18 ]. In addition to these phosphorylation events, proteomic analyses have revealed various phosphorylation sites in METTL3 and METTL14.…”

STM2457 Inhibits Breast Cancer Tumorigenesis via the Inhibition of METTL3

“…N 6 -methyladenosine (m 6 A) is the most common epitranscriptomic modification present in mRNA. Increased m 6 A modification of oncogenic mRNA promotes breast tumorigenesis by regulating post-transcriptional events such as mRNA stability, alternative splicing, and transla- tion efficiency (Achour et al 2023;Bhattarai et al 2023). The m 6 A modification of mRNA is mediated by a methyltransferase complex consisting of three core subunits: Methyltransferase-like 3 (METTL3), METTL14, and Wilm's tumor-associated protein (WTAP) (Liu et al 2014).…”

“…Similarly, METTL3 promotes the mRNA stability of PD-L1 in breast cancer cells to evade tumor immune surveillance. Recently, METTL3 has been known to promote breast tumorigenesis by enhancing the translation efficiency of TAZ/EGFR mRNA and by regulating the alternative splicing of MYC mRNA (Achour et al 2023;Bhattarai et al 2023). Moreover, inhibition of METTL3 expression with shRNA or CRISPR/Cas9 reduces the invasion and colony formation and induces apoptosis in breast cancer cells, which suggests that the therapeutic potential of METTL3 inhibition in breast cancer (Cai et al 2018;Achour et al 2023;Bhattarai et al 2023).…”

“…Recently, METTL3 has been known to promote breast tumorigenesis by enhancing the translation efficiency of TAZ/EGFR mRNA and by regulating the alternative splicing of MYC mRNA (Achour et al 2023;Bhattarai et al 2023). Moreover, inhibition of METTL3 expression with shRNA or CRISPR/Cas9 reduces the invasion and colony formation and induces apoptosis in breast cancer cells, which suggests that the therapeutic potential of METTL3 inhibition in breast cancer (Cai et al 2018;Achour et al 2023;Bhattarai et al 2023). Recently, a highly potent and selective catalytic inhibitor of METTL3, STM2457, has been studied for treating cancers induced by METTL3 overexpression (Xiao et al 2023).…”