bims-rimeca 2022-01-09 papers

bims-rimeca

Biomed News

on RNA methylation in cancer

Issue of 2022–01–09
thirteen papers selected by
Sk Ramiz Islam, Saha Institute of Nuclear Physics

METTL3 promotes lung adenocarcinoma tumor growth and inhibits ferroptosis by stabilizing SLC7A11 m6A modification.
METTL3-Mediated m6A Modification of TIMP2 mRNA Promotes Podocyte Injury in Diabetic Nephropathy.
N6-methyladenosine Regulator-Mediated Immune Genes Identify Breast Cancer Immune Subtypes and Predict Immunotherapy Efficacy.
RNA N6-methyladenosine reader IGF2BP2 promotes lymphatic metastasis and epithelial-mesenchymal transition of head and neck squamous carcinoma cells via stabilizing slug mRNA in an m6A-dependent manner.
SMC1A regulated by KIAA1429 in m6A-independent manner promotes EMT progress in breast cancer.
ATXN2-mediated translation of TNFR1 promotes esophageal squamous cell carcinoma via m6A-dependent manner.
m6A regulator-mediated methylation modification patterns and tumor immune microenvironment in sarcoma.
Hypoxia-mediated YTHDF2 overexpression promotes lung squamous cell carcinoma progression by activation of the mTOR/AKT axis.
Low Expression of YTH Domain-Containing 1 Promotes Microglial M1 Polarization by Reducing the Stability of Sirtuin 1 mRNA.
The m6A methyltransferase METTL3 affects autophagy and progression of nasopharyngeal carcinoma by regulating the stability of lncRNA ZFAS1.
Inhibition of ALKBH5-mediated m6 A modification of PPARG mRNA alleviates H/R-induced oxidative stress and apoptosis in placenta trophoblast.
Induction of m6A methylation in adipocyte exosomal LncRNAs mediates myeloma drug resistance.
MYC, mitochondrial metabolism and O-GlcNAcylation converge to modulate the activity and subcellular localization of DNA and RNA demethylases.

Cancer Cell Int. 2022 Jan 07. 22(1): 11

METTL3 promotes lung adenocarcinoma tumor growth and inhibits ferroptosis by stabilizing SLC7A11 m6A modification.

Yiming Xu, Dandan Lv, Chao Yan, Hua Su, Xue Zhang, Yangfeng Shi, Kejing Ying.

   BACKGROUND: N6-methyladenosine (m6A) has emerged as a significant regulator of the progress of various cancers. However, its role in lung adenocarcinoma (LUAD) remains unclear. Here, we explored the biological function and underlying mechanism of methyltransferase-like 3 (METTL3), the main catalyst of m6A, in LUAD progression.
METHODS: The expression of m6A, METTL3, YTHDF1 and SLC7A11 were detected by immunochemistry or/and online datasets in LUAD patients. The effects of METTL3 on LUAD cell proliferation, apoptosis and ferroptosis were assessed through in vitro loss-and gain-of-function experiments. The in vivo effect on tumorigenesis of METTL3 was evaluated using the LUAD cell xenograft mouse model. MeRIP-seq, RNA immunoprecipitation and RNA stability assay were conducted to explore the molecular mechanism of METTL3 in LUAD.
RESULTS: The results showed that the m6A level, as well as the methylase METTL3 were both significantly elevated in LUAD patients and lung cancer cells. Functionally, we found that METTL3 could promote proliferation and inhibit ferroptosis in different LUAD cell models, while METTL3 knockdown suppressed LUAD growth in cell-derived xenografts. Mechanistically, solute carrier 7A11 (SLC7A11), the subunit of system Xc-, was identified as the direct target of METTL3 by mRNA-seq and MeRIP-seq. METTL3-mediated m6A modification could stabilize SLC7A11 mRNA and promote its translation, thus promoting LUAD cell proliferation and inhibiting cell ferroptosis, a novel form of programmed cell death. Additionally, we demonstrated that YTHDF1, a m6A reader, was recruited by METTL3 to enhance SLC7A11 m6A modification. Moreover, the expression of YTHDF1 and SLC7A11 were positively correlated with METTL3 and m6A in LUAD tissues.
CONCLUSIONS: These findings reinforced the oncogenic role of METTL3 in LUAD progression and revealed its underlying correlation with cancer cell ferroptosis; these findings also indicate that METTL3 is a promising novel target in LUAD diagnosis and therapy.

Keywords:  Ferroptosis; Lung adenocarcinoma; METTL3; N6-methyladenosine (m6a) modification; SLC7A11

DOI:  https://doi.org/10.1186/s12935-021-02433-6
Mol Ther. 2022 Jan 04. pii: S1525-0016(22)00002-8. [Epub ahead of print]

METTL3-Mediated m6A Modification of TIMP2 mRNA Promotes Podocyte Injury in Diabetic Nephropathy.

Ling Jiang, Xue-Qi Liu, Xue-Ru Hu, Li Gao, Han-Xu Zeng, Xian Wang, Yue-Bo Huang, Wei Zhu, Jia-Nan Wang, Jia-Gen Wen, Xiao-Ming Meng, Yong-Gui Wu.

Epigenetic changes are present in many physiological and pathological processes. The N6-methyladenosine (m6A) modification is the most common modification in eukaryotic mRNA. However, the role of m6A modification in diabetic nephropathy (DN) remains elusive. Here, we found that m6A modification was significantly upregulated in the kidney of type 1 and type 2 diabetic mice, which was caused by elevated levels of METTL3. Moreover, METTL3 is increased in podocyte of renal biopsy from patients with DN, which is related to renal function. METTL3 knockout significantly reduced the inflammation and apoptosis in HG-stimulated podocytes, while its overexpression significantly aggravated these responses in vitro. Podocyte-conditional knockout METTL3 significantly alleviated podocyte injury and albuminuria in STZ-induced diabetic mice. Therapeutically, silencing METTL3 with AAV9-shMETTL3 in vivo mitigated albuminuria and histopathological injury in STZ-induced diabetic mice and db/db mice. Mechanistically, METTL3 modulated Notch signaling via the m6A modification of TIMP2 in an insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2)-dependent manner and exerted pro-inflammatory and pro-apoptotic effects. In summary, this study suggested that METTL3-mediated m6A modification is an important mechanism of podocyte injury in DN. Targeting m6A through the writer enzyme METTL3 is a potential approach for the treatment of DN.

DOI: https://doi.org/10.1016/j.ymthe.2022.01.002
Front Genet. 2021 ;12 790888

N6-methyladenosine Regulator-Mediated Immune Genes Identify Breast Cancer Immune Subtypes and Predict Immunotherapy Efficacy.

Meng-Meng Zhang, Yi-Lin Lin, Wen-Feng Zeng, Yang Li, Yang Yang, Miao Liu, Ying-Jiang Ye, Ke-Wei Jiang, Shu Wang, Shan Wang.

  Breast cancer (BRCA) is a heterogeneous malignancy closely related to the tumor microenvironment (TME) cell infiltration. N6-methyladenosine (m6A) modification of mRNA plays a crucial regulator in regulating the immune microenvironment of BRCA. Immunotherapy represents a paradigm shift in BRCA treatment; however, lack of an appropriate approach for treatment evaluation is a significant issue in this field. In this study, we attempted to establish a prognostic signature of BRCA based on m6A-related immune genes and to investigate the potential association between prognosis and immunotherapy. We comprehensively evaluated the m6A modification patterns of BRCA tissues and non-tumor tissues from The Cancer Genome Atlas and the modification patterns with TME cell-infiltrating characteristics. Overall, 1,977 TME-related genes were identified in the literature. Based on LASSO and Cox regression analyses, the m6A-related immune score (m6A-IS) was established to characterize the TME of BRCA and predict prognosis and efficacy associated with immunotherapy. We developed an m6A-IS to effectively predict immune infiltration and the prognosis of patients with BRCA. The prognostic score model represented robust predictive performance in both the training and validation cohorts. The low-m6A-IS group was characterized by enhanced antigen presentation and improved immune checkpoint expression, further indicating sensitivity to immunotherapy. Compared with the patients in the high-score group, the overall survival rate after treatment in the low-score group was significantly higher in the testing and validation cohorts. We constructed an m6A-IS system to examine the ability of the m6A signature to predict the infiltration of immune cells of the TME in BRCA, and the m6A-IS system acted as an independent prognostic biomarker that predicts the response of patients with BRCA in immunotherapy.

Keywords:  N6-methyladenosine; breast cancer; immunotherapy; prediction; tumor microenvironment

DOI:  https://doi.org/10.3389/fgene.2021.790888
J Exp Clin Cancer Res. 2022 Jan 03. 41(1): 6

RNA N6-methyladenosine reader IGF2BP2 promotes lymphatic metastasis and epithelial-mesenchymal transition of head and neck squamous carcinoma cells via stabilizing slug mRNA in an m6A-dependent manner.

Dan Yu, Min Pan, Yanshi Li, Tao Lu, Zhihai Wang, Chuan Liu, Guohua Hu.

   BACKGROUND: Lymph node metastasis is the main cause of poor prognosis of head and neck squamous carcinoma (HNSCC) patients. N6-methyladenosine (m6A) RNA modification is an emerging epigenetic regulatory mechanism for gene expression, and as a novel m6A reader protein, IGF2BP2 has been implicated in tumor progression and metastasis. However, not much is currently known about the functional roles of IGF2BP2 in HNSCC, and whether IGF2BP2 regulates lymphatic metastasis through m6A modification in HNSCC remains to be determined.
METHODS: The expression and overall survival (OS) probability of m6A-related regulators in HNSCC were analyzed with The Cancer Genome Atlas (TCGA) dataset and GEPIA website tool, respectively. The expression levels of IGF2BP2 were measured in HNSCC tissues and normal adjacent tissues. To study the effects of IGF2BP2 on HNSCC cell metastasis in vitro and in vivo, gain- and loss- of function methods were employed. RIP, MeRIP, luciferase reporter and mRNA stability assays were performed to explore the epigenetic mechanism of IGF2BP2 in HNSCC.
RESULTS: We investigated 20 m6A-related regulators in HNSCC and discovered that only the overexpression of IGF2BP2 was associated with a poor OS probability and an independent prognostic factor for HNSCC patients. Additionally, we demonstrated that IGF2BP2 was overexpressed in HNSCC tissues, and significantly correlated to lymphatic metastasis and poor prognosis. Functional studies have shown that IGF2BP2 promotes both HNSCC cell migration as well as invasion via the epithelial-mesenchymal transition (EMT) process in vitro, and IGF2BP2 knockdown significantly inhibited lymphatic metastasis and lymphangiogenesis in vivo. Mechanistic investigations revealed that Slug, a key EMT-related transcriptional factor, is the direct target of IGF2BP2, and essential for IGF2BP2-regulated EMT and metastasis in HNSCC. Furthermore, we demonstrated that IGF2BP2 recognizes and binds the m6A site in the coding sequence (CDS) region of Slug and promotes its mRNA stability.
CONCLUSIONS: Collectively, our study uncovers the oncogenic role and potential mechanism of IGF2BP2, which serves as a m6A reader, in controlling lymphatic metastasis and EMT in HNSCC, suggesting that IGF2BP2 may act as a therapeutic target and prognostic biomarker for HNSCC patients with metastasis.

Keywords:  EMT; HNSCC; IGF2BP2; Lymphatic metastasis; N6-methyladenosine; Slug

DOI:  https://doi.org/10.1186/s13046-021-02212-1
Mol Ther Nucleic Acids. 2022 Mar 08. 27 133-146

SMC1A regulated by KIAA1429 in m6A-independent manner promotes EMT progress in breast cancer.

Xu Zhang, Xin-Yuan Dai, Jia-Yi Qian, Feng Xu, Zhang-Wei Wang, Tian Xia, Xu-Jie Zhou, Xiao-Xia Li, Liang Shi, Ji-Fu Wei, Qiang Ding.

  As a component of N6-methyladenosine (m6A) "writers," KIAA1429 was reported to promote breast cancer proliferation and growth in m6A-independent manners. However, the related mechanism of KIAA1429 in breast cancer metastasis has not been reported. In the present study, we found KIAA1429 could significantly promote the migration and invasion of breast cancer cells. Then we demonstrated that knockdown of KIAA1429 could impede breast cancer metastasis in nude mice in vivo. The level of SNAIL expression and epithelial-mesenchymal transition (EMT) progress was positively related with KIAA1429. Furthermore, we confirmed that the suppression of cell migration, invasion, and EMT progress by knockdown of KIAA1429 could be reversed by the upregulation of SNAIL. However, structural maintenance of chromosomes 1A (SMC1A), not KIAA1429, bound with the SNAIL promoter region directly and promoted the transcription of SNAIL. Then we confirmed that KIAA1429 could bind to the motif in the 3' UTR of SMC1A mRNA directly and enhance SMC1A mRNA stability. In conclusion, our study revealed a novel mechanism of the KIAA1429/SMC1A/SNAIL axis in the regulation of metastasis of breast cancer. Moreover, it first provided detailed investigation of how KIAA1429 regulated the targeted gene expression at posttranscriptional levels as an RNA binding protein unrelated to its m6A modification.

Keywords:  KIAA1429; SMC1A; SNAIL; breast cancer; metastasis

DOI:  https://doi.org/10.1016/j.omtn.2021.08.009
Mol Ther. 2022 Jan 04. pii: S1525-0016(22)00006-5. [Epub ahead of print]

ATXN2-mediated translation of TNFR1 promotes esophageal squamous cell carcinoma via m6A-dependent manner.

Rui Li, Lingxing Zeng, Hongzhe Zhao, Junge Deng, Ling Pan, Shaoping Zhang, Guandi Wu, Ying Ye, Jialiang Zhang, Jiachun Su, Yanfen Zheng, Shuang Deng, Ruihong Bai, Lisha Zhuang, Mei Li, Zhixiang Zuo, Dongxin Lin, Jian Zheng, Xudong Huang.

N6-methyladenosine (m6A) is the most prevalent RNA modification and the effect of its dysregulation on esophageal squamous cell carcinoma (ESCC) development remains unclear. Here, by performing transcriptome-wide m6A sequencing in 16 ESCC tissue samples, we identified the key roles of m6A in TNFRSF1A (also known as TNFR1)-mediated MAPK and NF-κB activation in ESCC. Mechanistically, a functional protein involved in m6A methylation, ATXN2, is identified that augments the translation of TNFRSF1A by binding to m6A-modified TNFRSF1A mRNA. Upregulation of TNFRSF1A protein level, a vital upstream switch for TNFRSF1A-mediated signaling events, activates the NF-κB and MAPK pathways and thus promotes ESCC development. Furthermore, TNFRSF1A m6A modifications and protein levels are upregulated in ESCC, and high levels of TNFRSF1A m6A and protein are correlated with poor ESCC patient survival. These results collectively indicate that the m6A- TNFRSF1A axis is critical for ESCC development and thus might serve as a potential druggable target.

DOI: https://doi.org/10.1016/j.ymthe.2022.01.006
Aging (Albany NY). 2022 Jan 03. 13(undefined):

m6A regulator-mediated methylation modification patterns and tumor immune microenvironment in sarcoma.

Zhehong Li, Junqiang Wei, Honghong Zheng, Xintian Gan, Mingze Song, Yafang Zhang, Lingwei Kong, Chao Zhang, Jilong Yang, Yu Jin.

   BACKGROUND: Studies have shown that the RNA N6-methyladenosine (m6A) modification patterns are extensively involved in the development of multiple tumors. However, the association between the m6A regulator expression patterns and the sarcoma tumor immune microenvironment (TIME) remains unclear.
METHODS: We systematically evaluated the m6A regulator expression patterns in patients with sarcoma based on known 23 m6A regulators. Different m6A regulator expression patterns were analyzed using gene set variation analysis and a single-sample gene set enrichment analysis algorithm. According to the results of consensus clustering, we classified the patients into four different clusters. Next, we subjected the four clusters to differential genetic analysis and established m6A-related differentially expressed genes (DEGs). We then calculated the m6A-related DEGs score and constructed the m6A-related gene signature, named m6A score. Finally, the 259 sarcoma samples were divided into high- and low-m6A score groups. We further evaluated the TIME landscape between the high- and low-m6A score groups.
RESULTS: We identified four different m6A modification clusters and found that each cluster had unique metabolic and immunological characteristics. Based on the 19 prognosis-related DEGs, we calculated the principal component analysis scores for each patient with sarcoma and classified them into high- and low-m6A score groups.
CONCLUSIONS: The m6A regulator expression patterns and complexity of the sarcoma TIME landscape are closely related to each other. Systematic evaluation of m6A regulator expression patterns and m6A scores in patients with sarcoma will enhance our understanding of TIME characteristics.

Keywords:  m6A modifications patterns; m6A regulators; sarcoma; tumor immune microenvironment (TIME)

DOI:  https://doi.org/10.18632/aging.203807
Cancer Cell Int. 2022 Jan 07. 22(1): 13

Hypoxia-mediated YTHDF2 overexpression promotes lung squamous cell carcinoma progression by activation of the mTOR/AKT axis.

Peng Xu, Kang Hu, Ping Zhang, Zhi-Gang Sun, Nan Zhang.

   BACKGROUND: N6-methyladenosine (m6A) is a dynamic and reversible internal RNA structure of eukaryotic mRNA. YTH domain family 2 (YTHDF2), an m6A-specific reader YTH domain family, plays fundamental roles in several types of cancer. However, the function of YTHDF2 in lung squamous cell carcinoma (LUSC) remains elusive.
METHODS: The knockdown and overexpression of YTHDF2 in LUSC cells were conducted to detect the biological characteristics of YTHDF2. In vivo assays, the role of YTHDF2 in tumor growth was further uncovered. In vitro assays, YTHDF2 was confirmed to be involved in activating the mTOR/AKT signaling and YTHDF2 overexpression induced the EMT process in LUSC. Clinically, immunohistochemical staining revealed the relationship between YTHDF2 expression levels and the clinicopathological characteristics of lung squamous cell carcinoma patients. Moreover, quantitative PCR (qPCR), western blot, CCK8 assay, transwell assay, and wound-healing assay were used to detect the expression level and function of YTHDF2 under hypoxia exposure in LUSC cells.
RESULTS: The results showed that hypoxia-mediated YTHDF2 overexpression promotes cell proliferation and invasion by activating the mTOR/AKT axis, and YTHDF2 overexpression induces the EMT process in LUSC. Moreover, YTHDF2 is closely associated with pN (pN- 37.0%, pN + 73.9%; P = 0.002) and pTNM stage (pI 50.0%, PII 43.3%, pIIIa 80.6%; P = 0.007), ultimately resulting in poor survival for LUSC patients.
CONCLUSION: In brief, the results highlight high-YTHDF2 expression predicted a worse prognosis of LUSC, while hypoxia-mediated YTHDF2 overexpression promotes lung squamous cell carcinoma progression by activation of the mTOR/AKT signaling pathway.

Keywords:  EMT; Hypoxia; LUSC; METTL14; YTHDF2; mTOR/AKT

DOI:  https://doi.org/10.1186/s12935-021-02368-y
Front Cell Neurosci. 2021 ;15 774305

Low Expression of YTH Domain-Containing 1 Promotes Microglial M1 Polarization by Reducing the Stability of Sirtuin 1 mRNA.

Hongxiu Zhou, Zongren Xu, Xingyun Liao, Shiyun Tang, Na Li, Shengping Hou.

  The N6-methyladenosine (m6A) modification is the most abundant posttranscriptional mRNA modification in mammalian cells and is dynamically modulated by a series of "writers," "erasers," and "readers." Studies have shown that m6A affects RNA metabolism in terms of RNA processing, nuclear export, translation, and decay. However, the role of the m6A modification in retinal microglial activation remains unclear. Here, we analyzed the single-cell RNA sequencing data of retinal cells from mice with uveitis and found that the m6A-binding protein YTH domain-containing 1 (YTHDC1) was significantly downregulated in retinal microglia in the context of uveitis. Further studies showed that YTHDC1 deficiency resulted in M1 microglial polarization, an increased inflammatory response and the promotion of microglial migration. Mechanistically, YTHDC1 maintained sirtuin 1 (SIRT1) mRNA stability, which reduced signal transducer and activator of transcription 3 (STAT3) phosphorylation, thus inhibiting microglial M1 polarization. Collectively, our data show that YTHDC1 is critical for microglial inflammatory response regulation and can serve as a target for the development of therapeutics for autogenic immune diseases.

Keywords:  RNA stability; SIRT1; YTHDC1; m6A; microglia cells

DOI:  https://doi.org/10.3389/fncel.2021.774305
Infect Agent Cancer. 2022 Jan 03. 17(1): 1

The m6A methyltransferase METTL3 affects autophagy and progression of nasopharyngeal carcinoma by regulating the stability of lncRNA ZFAS1.

Jiaojiao Peng, Hong Zheng, Feng Liu, Qi Wu, Shixi Liu.

   BACKGROUND: Nasopharyngeal carcinoma (NPC) is a malignant tumor originating from the epithelial cells of the nasopharyngeal mucosa of the head and neck. The role of long non-coding RNA and RNA methylation in NPC has received increasing attention. Therefore, this study aims to investigate the mechanism of lncRNA ZFAS1 in NPC and its relationship with RNA methylation, providing evidence for targeted therapy of NPC.
METHODS: Microarray arrays were used to screen the differentially expressed miRNAs in normal tissues and tumor tissues. QRT-PCR was used to quantify ZFAS1, miR-100-3p, ATG10, autophagy and epithelial-mesenchymal transition related genes. The interactive relationship between ZFAS1 and miR-100-3p was verified using dual-luciferase reporter gene assay and RIP assay. CCK-8, transwell and apoptosis were used to detect the occurrence of tumor cells after different treatments. The m6A modification test is used to verify the effect of METTL3 on ZFAS1. BALB/c mice and BALB/c nude mice are used to detect the effects of different treatments on tumor growth and immune escape in vivo.
RESULTS: ZFAS1 is upregulated in tumor tissues and NPC cells. N (6)-methyladenosine (m6A) is highly enriched in ZFAS1 and enhances its RNA stability. ZFAS1 is used as an oncogenic lncRNA, which can promote NPC cell proliferation, migration and tumor growth. In terms of mechanism, ZFAS1 up-regulates the expression of ATG10 by competitively adsorbing miR-100-3p and regulates the level of autophagy by inhibiting the PI3K/Akt signaling pathway to promote the proliferation and migration of NPC cells.
CONCLUSION: In short, our study verified the cancer-promoting effect of ZFAS1 in NPC and explained part of the reason for its upregulation. In addition, we confirmed that ZFAS1 can regulate the autophagy level of NPC cells through the PI3K/AKT pathway through miR-100-3p/ATG10 to affect tumor progression.

Keywords:  Autophagy; N6-methyladenosine; Nasopharyngeal carcinoma; lncRNA ZFAS1

DOI:  https://doi.org/10.1186/s13027-021-00411-1
Environ Toxicol. 2022 Jan 07.

Inhibition of ALKBH5-mediated m6 A modification of PPARG mRNA alleviates H/R-induced oxidative stress and apoptosis in placenta trophoblast.

Yongping Guo, Wenxia Song, Yali Yang.

  The alpha-ketoglutarate-dependent (ALKB) homolog 5 (ALKBH5), an m6 A demethylase, has been reported to be involved in the pathogenesis of preeclampsia (PE), but the exact mechanism requires further investigation. RT-qPCR or Western blotting were used to determine ALKBH5 and peroxisome proliferator-activated receptor gamma (PPARG) expression in placentas from PE patients and normal volunteers, as well as in HTR-8/SVneo cells treated with hypoxia/reoxygenation (H/R). Our results showed that the expression of ALKBH5 was significantly upregulated and PPARG was downregulated in preeclamptic placentas and H/R-treated cells. ALKBH5 interference reduced m6 A levels of PPARG mRNA, and increased PPARG mRNA stability and promoted PPARG translation level. In addition, ALKBH5 silencing increased the cell proliferation, migration, and vimentin protein level, and inhibited cell apoptosis, oxidative stress, and protein levels of endoglin (ENG) and E-cadherin in H/R-treated cells, whereas PPARG interference reversed these effects. Furthermore, PPARG repressed the H3K9me2 levels at activated leukocyte cell adhesion molecule (ALCAM) promoter region by increasing the expression and activity of lysine demethylase 3B (KDM3B). ALCAM inhibition reversed the effects of PPARG overexpression on H/R-treated cell functions. PKF115-584 suppressed the effects of ALKBH5 interference on the behaviors of H/R-treated cells. Finally, inhibition of ALKBH5 alleviates PE-like features in pregnant mice. Inhibition of ALKBH5 promotes KDM3B-mediated ALCAM demethylation by facilitating PPARG mRNA m6 A modification, and further activates the Wnt/β-catenin pathway, and in turn alleviates PE progression.

Keywords:  ALCAM; ALKBH5; KDM3B; PPARG; preeclampsia; the Wnt/β-catenin pathway

DOI:  https://doi.org/10.1002/tox.23454
J Exp Clin Cancer Res. 2022 Jan 03. 41(1): 4

Induction of m6A methylation in adipocyte exosomal LncRNAs mediates myeloma drug resistance.

Zhiming Wang, Jin He, Duc-Hiep Bach, Yung-Hsing Huang, Zongwei Li, Huan Liu, Pei Lin, Jing Yang.

   BACKGROUND: Therapeutic resistance occurs in most patients with multiple myeloma (MM). One of the key mechanisms for MM drug resistance comes from the interaction between MM cells and adipocytes that inhibits drug-induced apoptosis in MM cells; MM cells reprogram adipocytes to morph into different characterizations, including exosomes, which are important for tumor-stroma cellular communication. However, the mechanism by which exosomes mediate the cellular machinery of the vicious cycle between MM cells and adipocytes remains unclear.
METHODS: Adipocytes were either isolated from bone marrow aspirates of healthy donors or MM patients or derived from mesenchymal stem cells. Co-culturing normal adipocytes with MM cells was used to generate MM-associated adipocytes. Exosomes were collected from the culture medium of adipocytes. Annexin V-binding and TUNEL assays were performed to assess MM cell apoptosis. Methyltransferase activity assay and dot blotting were used to access the m6A methylation activity of methyltransferase like 7A (METTL7A). RIP, MeRIP-seq, and RNA-protein pull down for assessing the interaction between long non-cording RNAs (LncRNAs) and RNA binding proteins were performed. Adipocyte-specific enhancer of zeste homolog 2 (EZH2) knockout mice and MM-xenografted mice were used for evaluating MM therapeutic response in vivo.
RESULTS: Exosomes collected from MM patient adipocytes protect MM cells from chemotherapy-induced apoptosis. Two LncRNAs in particular, LOC606724 and SNHG1, are significantly upregulated in MM cells after exposure to adipocyte exosomes. The raised LncRNA levels in MM cells are positively correlated to worse outcomes in patients, indicating their clinical relevancy in MM. The functional roles of adipocyte exosomal LOC606724 or SNHG1 in inhibition of MM cell apoptosis are determined by knockdown in adipocytes or overexpression in MM cells. We discovered the interactions between LncRNAs and RNA binding proteins and identified methyltransferase like 7A (METTL7A) as an RNA methyltransferase. MM cells promote LncRNA package into adipocyte exosomes through METTL7A-mediated LncRNA m6A methylation. Exposure of adipocytes to MM cells enhances METTL7A activity in m6A methylation through EZH2-mediated protein methylation.
CONCLUSION: This study elucidates an unexplored mechanism of how adipocyte-rich microenvironment exacerbates MM therapeutic resistance and indicates a potential strategy to improve therapeutic efficacy by blocking this vicious exosome-mediated cycle.

Keywords:  Adipocytes; Exosomes; LncRNA m6A Methylation; Myeloma; Therapeutics

DOI:  https://doi.org/10.1186/s13046-021-02209-w
Leukemia. 2022 Jan 08.

MYC, mitochondrial metabolism and O-GlcNAcylation converge to modulate the activity and subcellular localization of DNA and RNA demethylases.

An-Ping Lin, Zhijun Qiu, Purushoth Ethiraj, Binu Sasi, Carine Jaafar, Dinesh Rakheja, Ricardo C T Aguiar.

Mitochondria can function as signaling organelles, and part of this output leads to epigenetic remodeling. The full extent of this far-reaching interplay remains undefined. Here, we show that MYC transcriptionally activates IDH2 and increases alpha-ketoglutarate (αKG) levels. This regulatory step induces the activity of αKG-dependent DNA hydroxylases and RNA demethylases, thus reducing global DNA and RNA methylation. MYC, in a IDH2-dependent manner, also promotes the nuclear accumulation of TET1-TET2-TET3, FTO and ALKBH5. Notably, this subcellular movement correlated with the ability of MYC, in an IDH2-dependent manner, and, unexpectedly, of αKG to directly induce O-GlcNAcylation. Concordantly, modulation of the activity of OGT and OGA, enzymes that control the cycling of this non-canonical mono-glycosylation, largely recapitulated the effects of the MYC-IDH2-αKG axis on the subcellular movement of DNA and RNA demethylases. Together, we uncovered a hitherto unsuspected crosstalk between MYC, αKG and O-GlcNAcylation which could influence the epigenome and epitranscriptome homeostasis.

DOI: https://doi.org/10.1038/s41375-021-01489-7