PLEKHA4 Promotes Wnt/β-Catenin Signaling–Mediated G1–S Transition and Proliferation in Melanoma

Abstract

Despite recent promising advances in targeted therapies and immunotherapies, patients with melanoma incur substantial mortality. In particular, inhibitors targeting BRAF-mutant melanoma can lead to resistance, and no targeted therapies exist for NRAS-mutant melanoma, motivating the search for additional therapeutic targets and vulnerable pathways. Here we identify a regulator of Wnt/β-catenin signaling, PLEKHA4, as a factor required for melanoma proliferation and survival. PLEKHA4 knockdown in vitro decreased Dishevelled levels, attenuated Wnt/β-catenin signaling, and blocked progression through the G1–S cell-cycle transition. In mouse xenograft and allograft models, inducible PLEKHA4 knockdown attenuated tumor growth in BRAF- and NRAS-mutant melanomas and exhibited an additive effect with the clinically used inhibitor encorafenib in a BRAF-mutant model. As an E3 ubiquitin ligase regulator with both lipid- and protein-binding partners, PLEKHA4 presents several opportunities for targeting with small molecules. Our work identifies PLEKHA4 as a promising drug target for melanoma and clarifies a controversial role for Wnt/β-catenin signaling in the control of melanoma proliferation. Significance: This study establishes that melanoma cell proliferation requires the protein PLEKHA4 to promote pathologic Wnt signaling for proliferation, highlighting PLEKHA4 inhibition as a new avenue for the development of targeted therapies.

Proximity labeling reveals spatial regulation of the anaphase-promoting complex/cyclosome by a microtubule adaptor

“…Toward this effort, we have centered on poorly characterized members of the PLEKHA subfamily of pleckstrin homology domain-containing proteins. Previously, we found that PLEKHA4/kramer regulates Wnt signaling pathways in mammalian cells and in Drosophila and promotes proliferation in melanoma by antagonizing the polyubiquitination of Dishevelled by the Cullin 3–KLHL12 E3 ligase (Shami Shah et al, 2019, 2021). The PLEKHA4 paralog PLEKHA5 shares a similar multidomain architecture ( Figure 1A ) and has been linked to proliferation and metastasis in several disease models (Jilaveanu et al, 2015; Liu et al, 2020; Nagamura et al, 2021), though underlying mechanisms remained unknown, prompting us to investigate its molecular properties and cellular functions.…”

“…PLEKHA5 is a member of the PLEKHA4–7 protein family, several members of which are linked to cancer or cancer-related cellular processes such as proliferation or migration. PLEKHA4 levels are elevated in melanoma compared to healthy melanocytes, and depletion of PLEKHA4 attenuates melanoma cell proliferation in vitro and tumor xenograft growth in vivo (Shami Shah et al, 2021). PLEKHA7 is upregulated in colorectal cancer and supports the growth, adhesion, and invasion of KRAS-mutant colorectal cancer cells (Jeung et al, 2021).…”

Proximity Labeling Reveals Spatial Regulation of the Anaphase-Promoting Complex/Cyclosome by a Microtubule Adaptor

“…Toward this effort, we have centered on poorly characterized members of the PLEKHA subfamily of pleckstrin homology domain-containing proteins. Previously, we found that PLEKHA4/kramer regulates Wnt signaling pathways in mammalian cells and in Drosophila and promotes proliferation in melanoma by antagonizing the polyubiquitination of Dishevelled by the Cullin 3–KLHL12 E3 ligase. , The PLEKHA4 paralog PLEKHA5 shares a similar multidomain architecture (Figure A) and has been linked to proliferation and metastasis in several disease models, − although underlying mechanisms remained unknown, prompting us to investigate its molecular properties and cellular functions.…”

Characterization of Enterovirus Associated m6A RNA Methylation in Children With Neurological Symptoms: A Prospective Cohort Study

“…Previous study demonstrated that PLEKHA4 was a signaling strength modulator in Wnt signaling pathway, which controls key cell fate decisions in the development of multicellular eukaryotes ( Shami Shah et al, 2019 ). One study about Melanoma found that, PLEKHA4 was required for melanoma proliferation and survival, PLEKHA4 knockdown could attenuate tumor growth and enhance the effect of clinically used inhibitor encorafenib ( Shami Shah et al, 2021 ). We speculated that PLEKHA4 and related Wnt signaling may also involve with EV-induced neuron damage.…”