In:
PLOS ONE, Public Library of Science (PLoS), Vol. 16, No. 1 ( 2021-1-29), p. e0237554-
Abstract:
SLFN11 has recently been reported to execute cancer cells harboring replicative stress induced by DNA damaging agents. However, the roles of SLFN11 under physiological conditions remain poorly understood. Germinal center B-cells (GCBs) undergo somatic hypermutations and class-switch recombination, which can cause physiological genotoxic stress. Hence, we tested whether SLFN11 expression needs to be suppressed in GCBs during B-cell development. Objective To clarify the expression profile of SLFN11 in different developmental stages of B-cells and B-cell-derived cancers. Methods We analyzed the expression of SLFN11 by mining cell line databases for different stages of normal B-cells and various types of B-cell-derived cancer cell lines. We performed dual immunohistochemical staining for SLFN11 and B-cell specific markers in normal human lymphatic tissues. We tested the effects of two epigenetic modifiers, an EZH2 inhibitor, tazemetostat (EPZ6438) and a histone deacetylase inhibitor, panobinostat (LBH589) on SLFN11 expression in GCB-derived lymphoma cell lines. We also examined the therapeutic efficacy of these drugs in combination with cytosine arabinoside and the effects of SLFN11 on the efficacy of cytosine arabinoside in SLFN11-overexpressing cells. Results SLFN11 mRNA level was found low in both normal GCBs and GCB-DLBCL (GCB like-diffuse large B-cell lymphoma). Immunohistochemical staining showed low SLFN11 expression in GCBs and high SLFN11 expression in plasmablasts and plasmacytes. The EZH2 and HDAC epigenetic modifiers upregulated SLFN11 expression in GCB-derived lymphoma cells and made them more susceptible to cytosine arabinoside. SLFN11 overexpression further sensitized GCB-derived lymphoma cells to cytosine arabinoside. Conclusions The expression of SLFN11 is epigenetically suppressed in normal GCBs and GCB-derived lymphomas. GCB-derived lymphomas with low SLFN11 expression can be treated by the combination of epigenetic modifiers and cytosine arabinoside.
Type of Medium:
Online Resource
ISSN:
1932-6203
DOI:
10.1371/journal.pone.0237554
DOI:
10.1371/journal.pone.0237554.g001
DOI:
10.1371/journal.pone.0237554.g002
DOI:
10.1371/journal.pone.0237554.g003
DOI:
10.1371/journal.pone.0237554.g004
DOI:
10.1371/journal.pone.0237554.g005
DOI:
10.1371/journal.pone.0237554.s001
DOI:
10.1371/journal.pone.0237554.s002
DOI:
10.1371/journal.pone.0237554.s003
DOI:
10.1371/journal.pone.0237554.s004
DOI:
10.1371/journal.pone.0237554.s005
DOI:
10.1371/journal.pone.0237554.s006
DOI:
10.1371/journal.pone.0237554.s007
DOI:
10.1371/journal.pone.0237554.s008
DOI:
10.1371/journal.pone.0237554.s009
DOI:
10.1371/journal.pone.0237554.r001
DOI:
10.1371/journal.pone.0237554.r002
DOI:
10.1371/journal.pone.0237554.r003
DOI:
10.1371/journal.pone.0237554.r004
DOI:
10.1371/journal.pone.0237554.r005
DOI:
10.1371/journal.pone.0237554.r006
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2021
detail.hit.zdb_id:
2267670-3
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