Targeting cancer stemness mediated by <scp>BMI1</scp> and <scp>MCL1</scp> for non‐small cell lung cancer treatment

Lin, Erh-Hsuan; Hsu, Jhen-Wei; Lee, Ting-Fang; Hsu, Chiung-Fang; Lin, Tsung-Hsien; Jan, Yi-Hua; Chang, Hsiu-Ju; Cheng, Chunming; Hsu, Hao-Lin; Chen, Weiwei; Chen, Bo-Hung; Tsai, Henry J.; Li, Jung-Jung; Huang, Chi Ying F.; Chuang, Shuang‐En; Chang, Jia‐Ming; Hsiao, Michael; Wu, Cheng‐Wen

doi:10.1111/jcmm.17453

Cited by 6 publications

(3 citation statements)

References 52 publications

(154 reference statements)

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“…Existing studies have also conducted preliminary exploration into the role of BMI1 in NSCLC progression and chemotherapy drug resistance [40,41]. In this study, we observed a signi cant negative correlation between the expression of SOX4 and BMI1 in NSCLC tissues, and patients with high expression of both had worse prognoses.…”

Section: Discussionmentioning

confidence: 48%

SOX4-BMI1 Axis Promotes Non-Small Cell Lung Cancer Progression and Facilitates Angiogenesis by Suppressing ZNF24

Tian,

Wen,

Zhang

et al. 2024

Preprint

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The incidence of lung cancer has become the highest among all cancer types globally, also standing as a leading cause of cancer-related deaths. Lung cancer is broadly divided into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), with the latter accounting for 85% of total cases. SRY-box transcription factor 4 (SOX4), a crucial transcription factor, has been found to play a key role in the development of various cancers. However, the association between SOX4 and NSCLC is still unclear. This study investigated the clinical relevance of SOX4 and its potential mechanisms in the progression of NSCLC. Analysis of our NSCLC patient cohort revealed a significant increase in SOX4 levels in cancerous tissues, indicating its role as an independent prognostic indicator for NSCLC. In vitro experiments demonstrated that elevated SOX4 expression facilitated NSCLC cell migration, invasion, and EMT. Functionally, SOX4 drives NSCLC progression by enhancing the transcription and expression of B-cell-specific moloney leukemia virus insertion site 1 (BMI1). The oncogenic impact of SOX4-induced BMI1 expression on NSCLC advancement was validated through both in vivo and in vitro studies. Additionally, our findings showed that BMI1 promoted the ubiquitination of histone H2A (H2Aub), leading to decreased zinc finger protein 24 (ZNF24) expression, which subsequently triggered vascular endothelial growth factor A (VEGF-A) secretion in NSCLC cells, thereby promoting NSCLC angiogenesis. Moreover, we evaluated the therapeutic potential of a BMI1 inhibitor in combination with Bevacizumab for NSCLC treatment using orthotopic models. The data presented in our study reveal a previously unrecognized role of the SOX4-BMI1 axis in promoting NSCLC progression and angiogenesis. This research significantly contributes to our knowledge of the interplay between SOX4 and BMI1 in NSCLC, potentially paving the way for the development of targeted therapies for this disease.

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Section: Discussionmentioning

confidence: 48%

SOX4-BMI1 Axis Promotes Non-Small Cell Lung Cancer Progression and Facilitates Angiogenesis by Suppressing ZNF24

Tian,

Wen,

Zhang

et al. 2024

Preprint

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“…Zhou et al found targeting c-KIT can inhibit the growth and invasion of gefitinib-resistant NSCLC cells by reducing cancer stemness, EMT, and acquired drug resistance [ 67 ]. In lung cancer, MCL1 has been suggested to play a key role in cancer stem cells, including invasion, chemotherapy resistance, and tumorigenesis [ 68 ]. In NSCLC patients with EGFR mutations, the BIM deletion polymorphism results in an inherent resistance or reduced sensitivity to EGFR TKIs [ 69 ].…”

Section: Discussionmentioning

confidence: 99%

Exosomal hsa-miR-151a-3p and hsa-miR-877-5p are potential novel biomarkers for predicting bone metastasis in lung cancer

Zhao,

Jia,

Wang

et al. 2023

Aging

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Exosomal miRNAs (exo-miRNAs) have arisen as novel diagnostic biomarkers for various cancers. However, few reports on exo-miRNAs related to bone metastasis (BM) in lung cancer exist. This study aims to screen out key exo-miRNAs and estimate their prognostic values for predicting BM in lung cancer. The differentially expressed exo-miRNAs between the highly-metastatic (95D) and lowly-metastatic (A549) human lung cancer cell lines were comprehensively analyzed using high-throughput sequencing followed by bioinformatic analyses. 29 candidate exo-miRNAs were identified, and 101 BM-related target genes were predicted. Enrichment analysis revealed that these target genes were mainly involved in regulating transcription and pathways in cancer. An exosomal miRNA-mRNA regulatory network consisting of 7 key miRNAs and 10 hub genes was constructed. Further function analysis indicated that these 10 hub genes were mainly enriched in regulating cancer’s apoptosis and central carbon metabolism. The survival analysis indicated that 7 of 10 hub genes were closely related to prognosis. Mutation analysis showed that lung cancer patients presented certain genetic alterations in the 7 real hub genes. GSEA for a single hub gene suggested that 6 of 7 real hub genes had close associations with lung cancer development. Finally, ROC analysis revealed that hsa-miR-151a-3p and hsa-miR-877-5p provided high diagnostic accuracy in discriminating patients with bone metastasis (BM+) from patients without bone metastasis (BM-). These findings provided a comprehensive analysis of exo-miRNAs and target genes in the regulatory network of BM in lung cancer. In particular, hsa-miR-151a-3p and hsa-miR-877-5p may be novel biomarkers for predicting BM in lung cancer.

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“…As a heterodimers RING E3, BMI1 can induce H2A ubiquitylation at Lys 119. BMI1 can induce ubiquitination and degradation of NLR family CARD domain containing 5 (NLRC5), given that BMI1 can facilitate immune escape in NSCLC [ 58 , 62 ]. Thyroid Hormone Receptor Interacting Protein 12 (TRIP12), a HECT E3, also known as Ubiquitin Ligase for ARF (ULF) [ 63 ], ubiquitinates and degrades nuclear factor of activated T cells 1 (NFATc1), thereby downregulating PD-1 expression, resulting in increasing cancer infiltrating CD8 + T cells and inhibition in LLC growth in mice [ 64 ].…”

Section: Advanced Researches On the Functions Of E3 Ligases In Lung C...mentioning

confidence: 99%

Advances of E3 ligases in lung cancer

Yu,

Zhao,

Xie

2024

Biochemistry and Biophysics Reports

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Targeting cancer stemness mediated by BMI1 and MCL1 for non‐small cell lung cancer treatment

Cited by 6 publications

References 52 publications

SOX4-BMI1 Axis Promotes Non-Small Cell Lung Cancer Progression and Facilitates Angiogenesis by Suppressing ZNF24

SOX4-BMI1 Axis Promotes Non-Small Cell Lung Cancer Progression and Facilitates Angiogenesis by Suppressing ZNF24

Exosomal hsa-miR-151a-3p and hsa-miR-877-5p are potential novel biomarkers for predicting bone metastasis in lung cancer

Advances of E3 ligases in lung cancer

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