RNA modification writer expression profiles predict clinical outcomes and guide neoadjuvant immunotherapy in non-small cell lung cancer

Zhou, Bolun; Bie, Fenglong; Zang, Ruochuan; Zhang, Moyan; Song, Peng; Liu, Lei; Peng, Yue; Bai, Guangyu; Zhao, Jun; Gao, Shugeng

doi:10.1016/j.ebiom.2022.104268

Cited by 17 publications

(12 citation statements)

References 47 publications

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“…Additionally, highly expressed KIAA1429 showed worse clinical outcomes in patients with DLBCL with DHL, who exhibited a limited response to standard R-CHOP chemoimmunotherapy and tended to present poor prognosis [ 23 ], suggesting that KIAA1429 may be a predictor to guide the prognosis of DLBCL. Previous studies have demonstrated the oncogenic role of KIAA1429 in various human cancers, including gastric cancer [ 42 ], non-small cell lung cancer [ 43 ], breast cancer [ 44 ], and liver cancer [ 45 ], but not in DLBCL. Our results revealed that KIAA1429 expression was observed at high levels in DLBCL patient specimens and correlated with the clinical features and poor prognosis.…”

Section: Discussionmentioning

confidence: 99%

KIAA1429-mediated m6A modification of CHST11 promotes progression of diffuse large B-cell lymphoma by regulating Hippo–YAP pathway

et al. 2023

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Background N6-methyladenosine (m6A) has been shown to participate in various essential biological processes by regulating the level of target genes. However, the function of m6A modification mediated by KIAA1429 [alias virus-like m6A methyltransferase-associated protein (VIRMA)] during the progression of diffuse large B-cell lymphoma (DLBCL) remains undefined. Methods The expression and clinical significance of KIAA1429 were verified by our clinical data. CRISPR/Cas9 mediated KIAA1429 deletion, and CRISPR/dCas9-VP64 for activating endogenous KIAA1429 was used to evaluate its biological function. RNA sequencing (RNA-seq), methylated RNA immunoprecipitation sequencing (MeRIP-seq), RNA immunoprecipitation (RIP) assays, luciferase activity assay, RNA stability experiments, and co-immunoprecipitation were performed to investigate the regulatory mechanism of KIAA1429 in DLBCL. Tumor xenograft models were established for in vivo experiments. Results Dysregulated expression of m6A regulators was observed, and a novel predictive model based on m6A score was established in DLBCL. Additionally, elevated KIAA1429 expression was associated with poor prognosis of patients with DLBCL. Knockout of KIAA1429 repressed DLBCL cell proliferation, facilitated cell cycle arrest in the G2/M phase, induced apoptosis in vitro, and inhibited tumor growth in vivo. Furthermore, carbohydrate sulfotransferase 11 (CHST11) was identified as a downstream target of KIAA1429, which mediated m6A modification of CHST11 mRNA and then recruited YTHDF2 for reducing CHST11 stability and expression. Inhibition of CHST11 diminished MOB1B expression, resulting in inactivation of Hippo–YAP signaling, reprogramming the expression of Hippo target genes. Conclusions Our results revealed a new mechanism by which the Hippo–YAP pathway in DLBCL is inactivated by KIAA1429/YTHDF2-coupled epitranscriptional repression of CHST11, highlighting the potential of KIAA1429 as a novel predictive biomarker and therapeutic target for DLBCL progression.

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Section: Discussionmentioning

confidence: 99%

KIAA1429-mediated m6A modification of CHST11 promotes progression of diffuse large B-cell lymphoma by regulating Hippo–YAP pathway

et al. 2023

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“…Immune cells that are responsible for supporting tumors play a key role in this process 45 . ADAR1 may drive the transformation of normal cells into malignancies by regulating RNA editing and inhibiting immune responses 46,47 . Furthermore, ADAR1 expressed by tumor cells may participate in the crosstalk between the TME and tumor, thus contributing to a niche conducive to tumorigenesis and metastasis 23,47 .…”

Section: Discussionmentioning

confidence: 99%

“…45 ADAR1 may drive the transformation of normal cells into malignancies by regulating RNA editing and inhibiting immune responses. 46,47 tumorigenesis and metastasis. 23,47 Therefore, we analyzed the role of ADAR1 in the immune infiltration of LUAD.…”

Section: Discussionmentioning

confidence: 99%

ADAR1 is a prognostic biomarker and is correlated with immune infiltration in lung adenocarcinoma

Yang

Chen

et al. 2023

Cancer Medicine

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Background: Lung adenocarcinoma (LUAD) is a common subtype of non-small cell lung cancer with high morbidity and mortality rates and is usually detected at advanced stages because of the early onset of metastasis. Adenosine deaminase RNA-specific 1 (ADAR1) is an RNA editing enzyme that catalyzes the important physiological process of adenosine-to-inosine editing and has been shown to participate in the progression of LUAD. Increasing evidence has suggested that immune infiltration of the tumor immune microenvironment has prognostic value for most human solid organ malignancies; however, much is unknown about the functions of ADAR1. Methods:The expression of ADAR1 was analyzed in The Cancer Genome Atlas -LUAD database and validated in our LUAD cohort. To assess the prognostic value of ADAR1, Kaplan-Meier survival analyses and Cox regression analyses were carried out in LUAD cohorts. The association between ADAR1 and LUAD immune infiltrates via analyses of cell-type identification by estimating relative subsets of known RNA transcripts. Furthermore, multiplex immunohistochemistry was used to confirm the relationship between ADAR1 expression and immune cells in the present cohort of patients with LUAD.Results: ADAR1 was highly expressed in LUAD tissues and closely correlated with lymph node metastasis (LNM) (p < 0.01), advanced tumor stage (p < 0.05), and poor patient prognosis (p < 0.01), thus indicating that increased ADAR1 contributed to the progression of LUAD. LUAD with high ADAR1 expression can metastasize to lymph nodes that express more ADAR1 than the primary lesion.In addition, M0 macrophages and M2 macrophages increased and CD4 + T cells decreased in LUAD tissues with high ADAR1 expression. And the expression of ADAR1 in lymph node metastases was negatively correlated with the contents of CD4 + T cells (p = 0.0017) and M1 macrophages (p = 0.0037). Conclusion:The findings of our study suggested that ADAR1 may be useful in predicting prognosis and LNM in LUAD, and may serve as a promising immunerelated molecular target for LUAD patients.

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“…M6A methylation has been shown to play an important role in many cancer types, such as head and neck cancer 46 , acute myeloid leukemia (AML) 47 , glioblastoma (GBM) 48 , nasopharyngeal carcinoma (NPC) 49 , breast cancer 50 , lung cancer 51 , gastric cancer 52 , pancreatic cancer 53 , bladder cancer 54 , hepatocellular cancer (HCC) 55 , colorectal cancer (CRC) 56 , endometrial cancer 57 etc (Fig. 2 ).…”

Section: The Double Sword Of M6a In Human Cancersmentioning

confidence: 99%

Novel insights into the interplay between m6A modification and programmed cell death in cancer

Chen¹,

Ye²,

Bai³

et al. 2023

Int. J. Biol. Sci.

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N6-methyladenosine (m6A) methylation, the most prevalent and abundant RNA modification in eukaryotes, has recently become a hot research topic. Several studies have indicated that m6A modification is dysregulated during the progression of multiple diseases, especially in cancer development. Programmed cell death (PCD) is an active and orderly method of cell death in the development of organisms, including apoptosis, autophagy, pyroptosis, ferroptosis, and necroptosis. As the study of PCD has become increasingly profound, accumulating evidence has revealed the mutual regulation of m6A modification and PCD, and their interaction can further influence the sensitivity of cancer treatment. In this review, we summarize the recent advances in m6A modification and PCD in terms of their interplay and potential mechanisms, as well as cancer therapeutic resistance. Our study provides promising insights and future directions for the examination and treatment of cancers.

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RNA modification writer expression profiles predict clinical outcomes and guide neoadjuvant immunotherapy in non-small cell lung cancer

Cited by 17 publications

References 47 publications

KIAA1429-mediated m6A modification of CHST11 promotes progression of diffuse large B-cell lymphoma by regulating Hippo–YAP pathway

KIAA1429-mediated m6A modification of CHST11 promotes progression of diffuse large B-cell lymphoma by regulating Hippo–YAP pathway

ADAR1 is a prognostic biomarker and is correlated with immune infiltration in lung adenocarcinoma

Novel insights into the interplay between m6A modification and programmed cell death in cancer

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