In:
PLOS Biology, Public Library of Science (PLoS), Vol. 21, No. 9 ( 2023-9-14), p. e3002256-
Abstract:
The eradication of cancer stem cells (CSCs) with drug resistance confers the probability of local tumor control after chemotherapy or targeted therapy. As the main drug resistance marker, ABCG2 is also critical for colorectal cancer (CRC) evolution, in particular cancer stem–like traits expansion. Hitherto, the knowledge about the expression regulation of ABCG2, in particular its upstream transcriptional regulatory mechanisms, remains limited in cancer, including CRC. Here, ABCG2 was found to be markedly up–regulated in CRC CSCs (cCSCs) expansion and chemo–resistant CRC tissues and closely associated with CRC recurrence. Mechanistically, TOX3 was identified as a specific transcriptional factor to drive ABCG2 expression and subsequent cCSCs expansion and chemoresistance by binding to −261 to −141 segments of the ABCG2 promoter region. Moreover, we found that TOX3 recruited WDR5 to promote tri–methylation of H3K4 at the ABCG2 promoter in cCSCs, which further confers stem–like traits and chemoresistance to CRC by co–regulating the transcription of ABCG2. In line with this observation, TOX3, WDR5, and ABCG2 showed abnormal activation in chemo–resistant tumor tissues of in situ CRC mouse model and clinical investigation further demonstrated the comprehensive assessment of TOX3, WDR5, and ABCG2 could be a more efficient strategy for survival prediction of CRC patients with recurrence or metastasis. Thus, our study found that TOX3–WDR5/ABCG2 signaling axis plays a critical role in regulating CRC stem–like traits and chemoresistance, and a combination of chemotherapy with WDR5 inhibitors may induce synthetic lethality in ABCG2–deregulated tumors.
Type of Medium:
Online Resource
ISSN:
1545-7885
DOI:
10.1371/journal.pbio.3002256
DOI:
10.1371/journal.pbio.3002256.g001
DOI:
10.1371/journal.pbio.3002256.g002
DOI:
10.1371/journal.pbio.3002256.g003
DOI:
10.1371/journal.pbio.3002256.g004
DOI:
10.1371/journal.pbio.3002256.g005
DOI:
10.1371/journal.pbio.3002256.g006
DOI:
10.1371/journal.pbio.3002256.g007
DOI:
10.1371/journal.pbio.3002256.s001
DOI:
10.1371/journal.pbio.3002256.s002
DOI:
10.1371/journal.pbio.3002256.s003
DOI:
10.1371/journal.pbio.3002256.s004
DOI:
10.1371/journal.pbio.3002256.s005
DOI:
10.1371/journal.pbio.3002256.s006
DOI:
10.1371/journal.pbio.3002256.s007
DOI:
10.1371/journal.pbio.3002256.s008
DOI:
10.1371/journal.pbio.3002256.s009
DOI:
10.1371/journal.pbio.3002256.s010
DOI:
10.1371/journal.pbio.3002256.s011
DOI:
10.1371/journal.pbio.3002256.s012
DOI:
10.1371/journal.pbio.3002256.s013
DOI:
10.1371/journal.pbio.3002256.s014
DOI:
10.1371/journal.pbio.3002256.s015
DOI:
10.1371/journal.pbio.3002256.s016
DOI:
10.1371/journal.pbio.3002256.s017
DOI:
10.1371/journal.pbio.3002256.s018
DOI:
10.1371/journal.pbio.3002256.s019
DOI:
10.1371/journal.pbio.3002256.s020
DOI:
10.1371/journal.pbio.3002256.s021
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2023
detail.hit.zdb_id:
2126773-X
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