Data from lncRNA <i>JPX</i> Promotes Tumor Progression by Interacting with and Destabilizing YTHDF2 in Cutaneous Melanoma

Abstract

<div>Abstract<p>Aberrant long noncoding RNAs just proximal to Xist (lncRNA <i>JPX</i>) expression levels have been detected in multiple tumors. However, whether <i>JPX</i> is involved in melanoma progression remains unclear. Our study showed that <i>JPX</i> expression is significantly increased in melanoma tissues and cell lines. To clarify the effect of <i>JPX</i> on cutaneous melanoma, we successfully generated <i>JPX</i>-overexpressing or <i>JPX</i>-knockdown A375 and A2058 cells. CCK-8, colony formation EdU, Transwell, and cell-cycle phase assays were performed, and subcutaneously implanted tumor models were used to determine the function of <i>JPX</i> in cutaneous melanoma. The results showed that <i>JPX</i> knockdown reduced the proliferation and migration of malignant melanoma cells both <i>in vitro</i> and <i>in vivo</i>. To further elucidate the molecular mechanism of <i>JPX</i>-induced cutaneous melanoma deterioration, we performed RNA pull-down, RNA immunoprecipitation, coimmunoprecipitation, Western blot, and RNA-sequence analyses. <i>JPX</i> can directly interact with YTHDF2 and impede the protection of YTHDF2 from ubiquitin-specific protease 10 (USP10), which promotes its deubiquitination. Thus, JPX decreases protein stability and promotes the degradation of YTHDF2, thereby stabilizing <i>BMP2</i> mRNA and activating AKT phosphorylation. Overall, our study revealed a novel effect of <i>JPX</i> on YTHDF2 ubiquitination, suggesting the possibility of blocking the <i>JPX</i>/USP10/YTHDF2/BMP2 axis as a prospective therapeutic approach for cutaneous melanoma.</p>Implications:<p>This study highlights the ubiquitination effect of USP10 and <i>JPX</i> on YTHDF2 in cutaneous melanoma, and proposes that the <i>JPX</i>/USP10/YTHDF2/BMP2 axis may be a prospective therapeutic target for cutaneous melanoma.</p></div>