Elsevier

Leukemia Research

Volume 111, December 2021, 106708
Leukemia Research

NFYB potentiates STK33 activation to promote cisplatin resistance in diffuse large B-cell lymphoma

https://doi.org/10.1016/j.leukres.2021.106708Get rights and content

Highlights

Abstract

Background

The aberrant expression of serine/threonine kinase 33 (STK33) has been implicated in cancers. However, its clinical significance and biological functions in diffuse large B cell lymphoma (DLBCL) remain largely unknown. In the present investigation, we delineated the expression of STK33 in DLBCL and its function in cisplatin resistance.

Methods

First, genes associated with drug resistance as well as occurrence in DLBCL were analyzed by bioinformatics, followed by correlation analysis between STK33 expression and clinical baseline information of patients with DLBCL. Further, cisplatin-resistant DLBCL cell lines were constructed, and changes in cell sensitivity to cisplatin treatment were examined after interfering the expression of STK33 in parental cells as well as in drug-resistant cells, respectively. Subsequently, the downstream signaling pathways of STK33 were analyzed. Finally, the upstream regulatory mechanism of STK33 was predicted by bioinformatics as well as experimentally validated.

Results

STK33 was overexpressed in the patients with DLBCL as well as in cisplatin-resistant DLBCL cells, and knockdown of STK33 significantly promoted sensitivity of resistant cells to cisplatin. Moreover, our further analysis revealed that STK33 promoted cisplatin resistance in DLBCL by activating the Hedgehog signaling pathway. We found in subsequent experiments that nuclear transcription factor Y subunit beta (NFYB) can bind to the STK33 promoter and thus promote STK33 expression.

Conclusions

The transcription factor NFYB expedites the transcription of SYK33 by binding to the STK33 promoter, thereby activating the Hedgehog signaling pathway in DLBCL cells, which in turn promotes the resistance of DLBCL cells to cisplatin.

Introduction

Diffuse large B cell lymphoma (DLBCL) is the most frequent diagnosed type of lymphoma in adults worldwide which constitutes about one-third of all non-Hodgkin lymphoma cases each year, posing a substantial socioeconomic burden disturbing millions of people [1]. There are mainly three subgroups of DLBCL, activated B-cell-like, germinal-center B-cell-like, and unclassified based on the cell of origin that are linked to the response to chemotherapy and targeted agents [2]. For patients with relapsed non-Hodgkin lymphoma with prior anthracycline exposure, the PSHAP regimen (pixantrone, cytarabine, prednisone, cisplatin) is applicable [3]. However, many patients develop resistance after treatment with standard chemotherapy, making researching the molecular mechanisms of DLBCL to develop effective treatments very important [4].

Serine/threonine kinase 33 (STK33), which was discovered by sequencing the human chromosome 11 region 11p15 and mouse chromosome 7, is expressed in various tissues, including testis, fetal lung and heart, and retina [5]. The overexpression of STK33 has been identified in many solid tumors, involving hypopharyngeal squamous cell carcinoma, lung cancers, and colorectal cancer [[6], [7], [8], [9], [10]]. More recently, STK33-dependent cisplatin resistance has been suggested to promote tumor growth in lung adenocarcinoma [11], implying the close correlation between STK33 expression and cisplatin resistance in cancers. Mechanistically, in gastric cancer, KLF4, a transcription factor, transcriptionally repressed STK33 expression, and gastric cancer cell invasion inhibited by KLF4 was reversed by upregulation of STK33 [12]. As a consequence, we postulated that STK33 regulates cisplatin resistance in DLBCL with the involvement of a transcription factor. In addition, the Hedgehog signaling pathway has been indicated to be activated in DLBCL, which contributed to tumor cell survival and proliferation [13]. The association between the Hedgehog signaling pathway and cisplatin resistance has been highlighted in lung adenocarcinoma and ovarian epithelial tumors [14,15]. In addition, aberrant activation of Hedgehog pathways is ubiquitously observed and established to modulate tumor growth, survival, and chemoresistance in DLBCL [16]. Nevertheless, its implication in DLBCL cisplatin resistance remains to be clarified. Thus, we determined the Hedgehog signaling pathway as the downstream pathway of STK33 in DLBCL.

In the present study, we explored how the alteration in STK33 expression in two DLBCL lines, OCI-Ly1 and SUDHL4, affects cisplatin resistance in vitro and in vivo and the induction of the Hedgehog signaling axis, and elucidated the upstream mechanism of STK33 expression in DLBCL. This study was set to provide a possible and reliable theory for cisplatin resistance in DLBCL.

Section snippets

Microarray analysis

Firstly, we downloaded DLBCL-related gene expression microarrays from the Gene Expression Omnibus (GEO) databases (http://www.ncbi.nlm.nih.gov/geo/): GSE57520 (containing three spleen tissues and four lymphoma tissues), GSE27255 (containing eight parental cells and six drug-resistant lymphoma cell lines), and GSE61516 (containing four parental cells and 20 doxorubicin-resistant lymphoma cells). The gene expression profiling was conducted using the Affymetrix Human Genome U133 Plus 2.0 array

STK33 is significantly associated with the development and drug resistance in DLBCL

First, we downloaded the DLBCL-related gene expression microarrays from the GEO database. We normalized and corrected the data using R Limma package and analyzed the differentially expressed genes. A total of 76, 193 and 297 differentially expressed genes were screened out, respectively (Fig. 1A-C). Four genes, STK33, AIG1, TET2, and MYBPH were found in the intersection (Fig. 1D). Then, we searched the expression of these four genes in the TCGA-DLBC database, and we found a significant

Discussion

In this study, we examined the underlying molecular basis for STK33 overexpression in DLBCL and delineated its function in cisplatin resistance. We found that expression of STK33 was frequently higher in tumors than in adjacent tissue. We also exhibited a positive correlation between STK33 expression and cisplatin resistance in DLBCL cells. In vitro and in vivo experiments demonstrated that STK33 expedited DLBCL cell resistance to cisplatin by activating the Hedgehog pathway, as evidenced by

Conclusion

In conclusion, we found here in the study that there was an overexpression of STK33 in DLBCL cell lines. Moreover, ectopic expression of STK33 induced by NFYB promoted the cisplatin resistance of DLBCL cells by activating the Hedgehog signaling. Our study may possibly provide a theoretical basis for overcoming cisplatin resistance in DLBCL.

Funding

This work was supported by National Natural Science Foundation of China (81900876).

Declaration of Competing Interest

The authors report no declarations of interest.

Acknowledgement

The authors are thankful to National Natural Science Foundation of China (81900876).

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