Upregulation of CRABP2 by TET1-mediated DNA hydroxymethylation attenuates mitochondrial apoptosis and promotes oxaliplatin resistance in gastric cancer

Tang, Xiaolong; Liang, Yong; Sun, Guangbin; He, Qin; Hou, Zhenyu; Jiang, Xingzhi; Gao, Peng; Qü, Hui

doi:10.1038/s41419-022-05299-2

Cited by 22 publications

(13 citation statements)

References 53 publications

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“…Furthermore, the positive correlation between CRABP2 and HIF1α protein expression in ovarian cancer tissues, particularly in chemotherapy-insensitive tumors, further supports the clinical relevance of this interaction. Interestingly, it has been reported that CRAPB2 accelerates ubiquitination-mediated BAX degradation in gastric cancer cells, thereby alleviating mitochondrial apoptosis and promoting oxaliplatin resistance [ 45 ]. Therefore, CRAPB2 may regulate the development of drug resistance in a variety of tumors through multiple mechanisms.…”

Section: Discussionmentioning

confidence: 99%

CRABP2 affects chemotherapy resistance of ovarian cancer by regulating the expression of HIF1α

Fu,

Zhang,

Wang

et al. 2024

Cell Death Dis

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Ovarian cancer is the most lethal malignancy among gynecologic cancers, and primary and secondary chemotherapy resistance is one of the important reasons for poor prognosis of ovarian cancer patients. However, the specifics of resistance to chemotherapy in ovarian cancer remain unclear. Herein, we find that the expression level of cellular retinoic acid binding protein 2 (CRABP2) is up-regulated in drug-resistant ovarian cancer tissues and cell lines, and the expression levels of CRABP2 in epithelial ovarian cancer tissues are closely related to tumor clinical stage and patients’ prognosis, suggesting that CRABP2 plays an important role in the progression of ovarian cancer and the corresponding ability of tumor to chemotherapy. With the in-depth study, we demonstrates that CRABP2 is related to the high metabolic activity in drug-resistant cells, and all-trans retinoic acid exacerbates this activity. Further molecular mechanism exploration experiments show that CRABP2 not only up-regulates the expression level of HIF1α, but also increases the localization of HIF1α in the nucleus. In drug-resistant ovarian cancer cells, knocking down HIF1α can block the resistance of CRABP2 to chemotherapy drugs in ovarian cancer cells. Taken together, our findings suggest for the first time that CRABP2 affects chemotherapy resistance of ovarian cancer by regulating the expression of HIF1α. This study provides a possible molecular mechanism for drug resistance and a possible molecular target for clinical treatment of ovarian cancer.

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Section: Discussionmentioning

confidence: 99%

CRABP2 affects chemotherapy resistance of ovarian cancer by regulating the expression of HIF1α

Fu,

Zhang,

Wang

et al. 2024

Cell Death Dis

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“…CRABP2 was identified as a TMB-related gene in SKCM, and the significance of CRABP2 for tumor prognosis was attempted to analyze from two immune-related aspects: TMB and immune infiltration [ 33 ]. In STAD, CRABP2 was highly expressed under TET1-mediated DNA hydroxymethylation, which was correlated with poor OS and promoted oxaliplatin resistance [ 48 ]. There is currently no research focusing on the role of CRABP2 in TGCT.…”

Section: Discussionmentioning

confidence: 99%

CRABP2 regulates infiltration of cancer-associated fibroblasts and immune response in melanoma

ZENG,

CHEN,

et al. 2024

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Finding biomarkers for immunotherapy is an urgent issue in cancer treatment. Cellular retinoic acid-binding protein 2 (CRABP2) is a controversial factor in the occurrence and development of human tumors. However, there is limited research on the relationship between CRABP2 and immunotherapy response. This study found that negative correlations of CRABP2 and immune checkpoint markers (PD-1, PD-L1, and CTLA-4) were observed in breast invasive carcinoma (BRCA), skin cutaneous melanoma (SKCM), stomach adenocarcinoma (STAD) and testicular germ cell tumors (TGCT). In particular, in SKCM patients who were treated with PD-1 inhibitors, high levels of CRABP2 predicted poor prognosis. Additionally, CRABP2 expression was elevated in cancer-associated fibroblasts (CAFs) at the single-cell level. The expression of CRABP2 was positively correlated with markers of CAFs, such as MFAP5, PDPN, ITGA11, PDGFRα/β and THY1 in SKCM. To validate the tumor-promoting effect of CRABP2 in vivo , SKCM xenograft mice models with CRABP2 overexpression have been constructed. These models showed an increase in tumor weight and volume. Enrichment analysis indicated that CRABP2 may be involved in immune-related pathways of SKCM, such as extracellular matrix (ECM) receptor interaction and epithelial-mesenchymal transition (EMT). The study suggests that CRABP2 may regulate immunotherapy in SKCM patients by influencing infiltration of CAFs. In conclusion, this study provides new insights into the role of CRABP2 in immunotherapy response. The findings suggest that CRABP2 may be a promising biomarker for PD-1 inhibitors in SKCM patients. Further research is needed to confirm these findings and to explore the clinical implications of CRABP2 in immunotherapy.

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“…57 Besides, enriched in the promoter region of CRABP2, TET1 can increase its expression, thereby inhibiting Bax-dependent apoptosis to induce oxaliplatin resistance in gastric cancer cells. 58 Interestingly, TET1 knockdown can cause lung cancer cells resistant to gefitinib. 59 Similarly, the knockdown of TET2 triggered resistance in BRCA2 deficient cells to multiple poly (ADP-ribose) polymerase (PARP) inhibitors and cisplatin.…”

Section: Dna Methylation and Drug Resistancementioning

confidence: 99%

Targeting epigenetic regulators to overcome drug resistance in cancers

Wang

2023

Sig Transduct Target Ther

119

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Drug resistance is mainly responsible for cancer recurrence and poor prognosis. Epigenetic regulation is a heritable change in gene expressions independent of nucleotide sequence changes. As the common epigenetic regulation mechanisms, DNA methylation, histone modification, and non-coding RNA regulation have been well studied. Increasing evidence has shown that aberrant epigenetic regulations contribute to tumor resistance. Therefore, targeting epigenetic regulators represents an effective strategy to reverse drug resistance. In this review, we mainly summarize the roles of epigenetic regulation in tumor resistance. In addition, as the essential factors for epigenetic modifications, histone demethylases mediate the histone or genomic DNA modifications. Herein, we comprehensively describe the functions of the histone demethylase family including the lysine-specific demethylase family, the Jumonji C-domain-containing demethylase family, and the histone arginine demethylase family, and fully discuss their regulatory mechanisms related to cancer drug resistance. In addition, therapeutic strategies, including small-molecule inhibitors and small interfering RNA targeting histone demethylases to overcome drug resistance, are also described.

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Upregulation of CRABP2 by TET1-mediated DNA hydroxymethylation attenuates mitochondrial apoptosis and promotes oxaliplatin resistance in gastric cancer

Cited by 22 publications

References 53 publications

CRABP2 affects chemotherapy resistance of ovarian cancer by regulating the expression of HIF1α

CRABP2 affects chemotherapy resistance of ovarian cancer by regulating the expression of HIF1α

CRABP2 regulates infiltration of cancer-associated fibroblasts and immune response in melanoma

Targeting epigenetic regulators to overcome drug resistance in cancers

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