NDLI: BMX, a specific HDAC8 inhibitor, with TMZ for advanced CRC therapy: a novel synergic effect to elicit p53-, β-catenin- and MGMT-dependent apoptotic cell death

Content Provider	Springer Nature : BioMed Central
Author	Ko, Huey-Jiun Chiou, Shean-Jaw Tsai, Cheng-Yu Loh, Joon-Khim Lin, Xin-Yi Tran, Thu-Ha Hou, Chia-Chung Cheng, Tai-Shan Lai, Jin-Mei Chang, Peter Mu-Hsin Wang, Feng-Sheng Su, Chun-Li Huang, Chi-Ying F. Hong, Yi-Ren
Abstract	Background Despite advances in treatment, patients with refractory colorectal cancer (CRC) still have poor long-term survival, so there is a need for more effective therapeutic options. Methods To evaluate the HDAC8 inhibition efficacy as a CRC treatment, we examined the effects of various HDAC8 inhibitors (HDAC8i), including BMX (NBM-T-L-BMX-OS01) in combination with temozolomide (TMZ) or other standard CRC drugs on p53 mutated HT29 cells, as well as wild-type p53 HCT116 and RKO cells. Results We showed that HDAC8i with TMZ cotreatment resulted in HT29 arrest in the S and G2/M phase, whereas HCT116 and RKO arrest in the G0/G1 phase was accompanied by high sub-G1. Subsequently, this combination approach upregulated p53-mediated MGMT inhibition, leading to apoptosis. Furthermore, we observed the cotreatment also enabled triggering of cell senescence and decreased expression of stem cell biomarkers. Mechanistically, we found down-expression levels of β-catenin, cyclin D1 and c-Myc via GSK3β/β-catenin signaling. Intriguingly, autophagy also contributes to cell death under the opposite status of β-catenin/p62 axis, suggesting that there exists a negative feedback regulation between Wnt/β-catenin and autophagy. Consistently, the Gene Set Enrichment Analysis (GSEA) indicated both apoptotic and autophagy biomarkers in HT29 and RKO were upregulated after treating with BMX. Conclusions BMX may act as a HDAC8 eraser and in combination with reframed-TMZ generates a remarkable synergic effect, providing a novel therapeutic target for various CRCs. Video Abstract
Related Links	https://biosignaling.biomedcentral.com/counter/pdf/10.1186/s12964-022-01007-x.pdf
Ending Page	19
Page Count	19
Starting Page	1
File Format	HTM / HTML
DOI	10.1186/s12964-022-01007-x
Journal	Cell Communication and Signaling
Issue Number	1
Volume Number	20
Language	English
Publisher	BioMed Central
Publisher Date	2022-12-27
Access Restriction	Open
Subject Keyword	Cell Biology Protein-Ligand Interactions Receptors Cytokines and Growth Factors HDAC8 inhibitor CRC TMZ MGMT β-catenin p53
Content Type	Text
Resource Type	Article
Subject	Biochemistry Cell Biology Molecular Biology
Journal Impact Factor	8.2/2023
5-Year Journal Impact Factor	8/2023

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BMX, a specific HDAC8 inhibitor, with TMZ for advanced CRC therapy: a novel synergic effect to elicit p53-, β-catenin- and MGMT-dependent apoptotic cell death

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