WTAP is a promising diagnosis and treatment biomarker that inhibits the proliferation and invasion of melanoma cells

Huixiu Lu, Yanli Zhang, Jiali Li, Dan Lou, Licui Li, Yunchuan Liang, Jianying Li,  Yaling Liu

Abstract:

Wilms’ tumour 1-associating protein (WTAP) is ubiquitously expressed in many tissues and plays an important role in physiological processes and tumour development. Here, we investigated the specific biological role and underlying mechanism of WTAP in melanoma. We determined the expression of WTAP and its correlation with clinicopathological features in paraffin-embedded tissues. We investigated the effects of WTAP on melanoma cells via a CCK-8 assay, a colony formation assay, an EdU assay, a transwell assay and subcutaneous xenograft experiments. We then applied RNA sequencing to further screen candidate targets, and NT5E was selected as the downstream gene of WTAP. Finally, a series of rescue assays together with nucleotidase assays and ELISA were adopted to confirm the function of NT5E in melanoma progression. We demonstrated that WTAP expression was downregulated in melanoma, which was associated with a poor prognosis, and that WTAP expression served as an independent predictor of melanoma survival. Functionally, WTAP hindered the proliferation, growth, migration and invasion of melanoma cells. Furthermore, NT5E was identified as the downstream effector of WTAP and was subsequently found to rescue the increased proliferation, migration and invasion of melanoma cells induced by WTAP deficiency. Moreover, knockdown of WTAP increased the expression of NT5E, MMP2 and N-cadherin, and simultaneous transfection with siNT5E reversed the increased expression of MMP2 and N-cadherin. Moreover, increased NT5E expression caused by forced WTAP inhibition in melanoma promoted the hydrolysis of AMP to produce more adenosine and further abrogated the secretion of IFN-γ by PBMCs. We found that WTAP expression is significantly downregulated and restrains the progression of melanoma via the downstream effects of NT5E on immunosuppression and molecular adhesion. This study revealed that WTAP plays a crucial inhibitory role in melanoma oncogenesis and highlighted WTAP as a potential novel diagnosis and therapeutic target for melanoma.