A novel TOX3-WDR5-ABCG2 signaling axis regulates the progression of colorectal cancer by accelerating stem-like traits and chemoresistance

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.

WD Repeat Domain 5 Inhibitors for Cancer Therapy: Not What You Think

“…Since 2014, potential applications for WDR5 inhibitors have accrued rapidly. Breast cancer [ 49 , 50 , 51 , 52 ], C/EBPα-mutant leukemias [ 17 ], MYC-driven cancers [ 53 ], pancreatic cancer [ 54 , 55 ], p53 gain-of-function mutant cancers [ 56 ], colorectal cancer [ 57 , 58 ], neuroblastoma [ 5 , 20 ], hepatocellular carcinoma [ 59 ], bladder cancer [ 60 , 61 ], rhabdoid tumors [ 62 ], multidrug-resistant cancers [ 63 ], and glioblastomas [ 64 ] are all cancer settings in which WDR5 inhibition has been proposed as a future therapy. More recently, a wide assortment of non-cancer applications have also been proposed, including improved in vitro fertilization in cattle [ 65 ], as well as treating aliments such as chronic kidney disease [ 66 ], neuropathic allodynia [ 67 ], Alzheimer’s [ 68 ], acute kidney injury [ 69 ], cardiac fibrosis [ 70 ], and atherosclerosis [ 71 ].…”