Wilms’ tumor 1-associating protein plays an aggressive role in diffuse large B-cell lymphoma and forms a complex with BCL6 via Hsp90

Abstract

BackgroundWilms’ tumor 1-associating protein (WTAP) is a nuclear protein, which is ubiquitously expressed in many tissues. Furthermore, in various types of malignancies WTAP is overexpressed and plays a role as an oncogene. The function of WTAP in diffuse large B-cell lymphoma (DLBCL), however, remains unclear.MethodsImmunohistochemistry was applied to evaluate the levels of WTAP expression in DLBCL tissues and normal lymphoid tissues. Overexpression and knock-down of WTAP in DLBCL cell lines, verified on mRNA and protein level served to analyze cell proliferation and apoptosis in DLBCL cell lines by flow cytometry. Finally, co-immunoprecipitation (Co-IP), IP, and GST-pull down assessed the interaction of WTAP with Heat shock protein 90 (Hsp90) and B-cell lymphoma 6 (BCL6) as well as determined the extend of its ubiquitinylation.ResultsWTAP protein levels were consistently upregulated in DLBCL tissues. WTAP promoted DLBCL cell proliferation and improved the ability to confront apoptosis, while knockdown of WTAP in DLBCL cell lines allowed a significant higher apoptosis rate after treatment with Etoposide, an anti-tumor drug. The stable expression of WTAP was depended on Hsp90. In line, we demonstrated that WTAP could form a complex with BCL6 via Hsp90 in vivo and in vitro.ConclusionWTAP is highly expressed in DLBCL, promoting growth and anti-apoptosis in DLBCL cell lines. WTAP is a client protein of Hsp90 and can appear in a complex with BCL6 and Hsp90 in DLBCL. Down-regulation of WTAP could improve the chemotherapeutic treatments in DLBCL.Electronic supplementary materialThe online version of this article (10.1186/s12964-018-0258-6) contains supplementary material, which is available to authorized users.

WTAP promotes osteosarcoma tumorigenesis by repressing HMBOX1 expression in an m6A-dependent manner

“…Actually, WTAP was reported as an oncogene in various cancers [37][38][39]42 . Recent studies reported that WTAP is strictly connected to a functional m 6 A methylation complex 43 .…”

“…In addition, accumulated studies identified the important role of WTAP in the progression of various cancers 37 . For example, WTAP function as oncogene in cholangiocarcinoma 38 , acute myeloid leukemia 39 , colon cancer 40 , ovarian cancer 41 , and diffuse large B-cell lymphoma 42 . Recent studies reported that WTAP is strictly connected to a functional m 6 A methylation complex 43 .…”

High expression of WTAP leads to poor prognosis of gastric cancer by influencing tumour‐associated T lymphocyte infiltration

“…In fact, WTAP overexpression is an important risk factor in many tumours . WTAP is widely expressed in various tissues and plays an important role in cell cycle regulation, RNA alternative splicing, m6A methylation modification, x‐chromosome inactivation, eye development, regulation of physiological balance and other physiological processes .…”

<p>WTAP is a prognostic marker of high-grade serous ovarian cancer and regulates the progression of ovarian cancer cells</p>

“…RNA-seq analysis revealed that with the depletion of both WTAP and KIAA1429, the nuclear/cytoplasmic ratio of 73% mRNAs was increased, indicating that WTAP was involved in mRNA export 19. Besides, its growth stimulating role has been elucidated in several cancers, including pancreatic ductal adenocarcinoma, renal cell carcinoma, and diffuse large B-cell lymphoma 10–12. However, the evidence of influence caused by WTAP on ovarian cancer is insufficient.…”

“…In renal cell carcinoma, WTAP promoted cancer proliferation via enhancing the stability of CDK2 mRNA by directly binding to CDK2 transcript 11. In diffuse large B-cell lymphoma, WTAP not only increased proliferation, but also counteracted Etoposide-mediated apoptosis, which indicated a poor chemotherapy sensitivity 12. Noticeably, WTAP gene is located on chromosome 6q25.3 in human, a region concerned to be associated with ovarian cancer 13…”