SET1A-Mediated Mono-Methylation at K342 Regulates YAP Activation by Blocking Its Nuclear Export and Promotes Tumorigenesis

Abstract

YAP, a key effector of Hippo pathway, is activated by its translocation from cytoplasm to nucleus to regulate gene expression and promote tumorigenesis. Although the mechanism by which YAP is suppressed in cytoplasm has been well-studied, how the activated YAP is sequestered in the nucleus remains unknown. Here, we demonstrate that YAP is a nucleocytoplasmic shuttling protein and its nuclear export is controlled by SET1A-mediated mono-methylation of YAP at K342, which disrupts the binding of YAP to CRM1. YAP mimetic methylation knockin mice are more susceptible to colorectal tumorigenesis. Clinically, YAP K342 methylation is reversely correlated with cancer survival. Collectively, our study identifies SET1A-mediated mono-methylation at K342 as an essential regulatory mechanism for regulating YAP activity and tumorigenesis.

MST4 kinase suppresses gastric tumorigenesis by limiting YAP activation via a non-canonical pathway

“…Together with these studies, our current work further demonstrates a complicated machinery for fine and tight control of YAP activity under various cellular contexts. Interestingly, some negative regulators of YAP, such as MST4 kinase characterized here, and the reported SET1A (Fang et al, 2018), RUNX3 (Qiao et al, 2016), and OTUD1 (Yao et al, 2018), were found to be down-regulated in different cancer specimens and to be associated with poor prognosis. Perhaps dysregulation of these YAP-related tumor suppressors could explain the hyperactivation of YAP in cancer cells without apparent change of the classic Hippo kinase cascade.…”

“…The Hippo–YAP pathway can respond to a wide range of stress signals, eventually leading to the manifestation of different states of YAP-dependent gene transcription. Recently, a burst of studies have identified various types of PTMs including ubiquitination, methylation, and O-GlcNAcylation to regulate YAP activation in Hippo-independent manners (Fang et al, 2018; Peng et al, 2017; Yao et al, 2018; Zhang et al, 2017, 2019). Together with these studies, our current work further demonstrates a complicated machinery for fine and tight control of YAP activity under various cellular contexts.…”

“…Meanwhile, quantitative analysis–based screening revealed mediators of YAP import/export machineries (Ege et al, 2018). PTMs, such as methylation, can also affect YAP nuclear export process (Fang et al, 2018). Consistent with these reports, here we found KPNA2 (importin α1), as well as KPNA1 (importin α5) and KPNA7 (importin α8), interact with YAP and mediate its nuclear import in mammals.…”

“…Despite various types of posttranslational modifications (PTMs) including dephosphorylation (Huang et al, 2013; Liu et al, 2013; Wang et al, 2012; Wilson et al, 2014), ubiquitination (Cho et al, 2020; Sun et al, 2019; Yao et al, 2018), methylation (Fang et al, 2018; Oudhoff et al, 2013), and O-GlcNAcylation (Peng et al, 2017; Zhang et al, 2017) that have been implicated in fine-tuning YAP activity, phosphorylation is regarded as a dominant manner of YAP regulation. The classic Hippo-YAP signaling features sequential phosphorylation of YAP at Ser127 (Zhang et al, 2008, 2015; Zhao et al, 2007) and Ser381/Ser384 (Zhao et al, 2010).…”

The role of ubiquitination in tumorigenesis and targeted drug discovery

“…[316][317][318][319][320] Ubiquitination in the Hippo-YAP signaling pathway In mammals, the Hippo signaling pathway can also maintain CSC stemness, regulate cell growth, control the size of organs and take part in tumorigenesis. 321,322 Ubiquitination also plays an important role in regulating the Hippo signaling pathway, with a variety of E3 ligases being identified. For example, CRL4DCAF1 negatively regulates the Hippo signaling pathway by ubiquitinating and degrading Lats1 while promoting the monoubiquitination of Lats2 and inhibiting its activity.…”