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YTHDF1 regulates the downstream players of the Wnt/β-catenin pathway.

N6-methyladenosine (m6A) is the most prevalent internal RNA modification in mammals that regulates homeostasis and function of modified RNA transcripts. Here, we aimed to investigate the role of YTH m6A RNA-binding protein 1 (YTHDF1), a key regulator of m6A methylation in gastric cancer tumorigenesis. Multiple bioinformatic analyses of different human cancer databases identified key m6A-associated genetic mutations that regulated gastric tumorigenesis. YTHDF1 was mutated in about 7% of patients with gastric cancer, and high expression of YTHDF1 was associated with more aggressive tumor progression and poor overall survival. Inhibition of YTHDF1 attenuated gastric cancer cell proliferation and tumorigenesis in vitro and in vivo. Mechanistically, YTHDF1 promoted the translation of a key Wnt receptor frizzled7 (FZD7) in an m6A-dependent manner, and mutated YTHDF1 enhanced expression of FZD7, leading to hyperactivation of the Wnt/β-catenin pathway and promotion of gastric carcinogenesis. Our results demonstrate the oncogenic role of YTHDF1 and its m6A-mediated regulation of Wnt/β-catenin signaling in gastric cancer, providing a novel approach of targeting such epigenetic regulators in this disease.Significance:This study provides a rationale for controlling translation of key oncogenic drivers in cancer by manipulating epigenetic regulators, representing a novel and efficient strategy for anticancer treatment.

Supplementary Materials and Methods

Supplementary Figure Legends

Identification of YTHDF1-regulated transcripts by RNA-seq, RIP-seq and MeRIP-seq. Related to Figure 3. This file contains six tabs: 1, RNA profiling revealed transcripts that were dysregulated upon YTHDF1 deficiency. 2, YTHDF1-binding genes revealed by RIP-seq within MGC-803 cells. 3, m6A peaks revealed by m6A-seq within MGC-803 cells. 4, The overlap of transcripts identified by YTHDF1 specific RIP-seq and MeRIP-seq. 5, The overlap of transcripts were enriched in Wnt and Hippo signaling pathways. 6, YTHDF1 candidate targets in the Hippo or Wnt pathways.

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N6-methyladenosine (m6A) is the most prevalent internal RNA modification in mammals that regulates homeostasis and function of modified RNA transcripts. Here, we aimed to investigate the role of YTH m6A RNA-binding protein 1 (YTHDF1), a key regulator of m6A methylation in gastric cancer tumorigenesis. Multiple bioinformatic analyses of different human cancer databases identified key m6A-associated genetic mutations that regulated gastric tumorigenesis. YTHDF1 was mutated in about 7% of patients with gastric cancer, and high expression of YTHDF1 was associated with more aggressive tumor progression and poor overall survival. Inhibition of YTHDF1 attenuated gastric cancer cell proliferation and tumorigenesis in vitro and in vivo. Mechanistically, YTHDF1 promoted the translation of a key Wnt receptor frizzled7 (FZD7) in an m6A-dependent manner, and mutated YTHDF1 enhanced expression of FZD7, leading to hyperactivation of the Wnt/β-catenin pathway and promotion of gastric carcinogenesis. Our results demonstrate the oncogenic role of YTHDF1 and its m6A-mediated regulation of Wnt/β-catenin signaling in gastric cancer, providing a novel approach of targeting such epigenetic regulators in this disease. Significance: This study provides a rationale for controlling translation of key oncogenic drivers in cancer by manipulating epigenetic regulators, representing a novel and efficient strategy for anticancer treatment.

N 6-Methyladenosine (m6A) is the most abundant RNA modification in mammal mRNAs and increasing evidence suggests the key roles of m6A in human tumorigenesis. However, whether m6A, especially its ‘reader’ YTHDF1, targets a gene involving in protein translation and thus affects overall protein production in cancer cells is largely unexplored. Here, using multi-omics analysis for ovarian cancer, we identified a novel mechanism involving EIF3C, a subunit of the protein translation initiation factor EIF3, as the direct target of the YTHDF1. YTHDF1 augments the translation of EIF3C in an m6A-dependent manner by binding to m6A-modified EIF3C mRNA and concomitantly promotes the overall translational output, thereby facilitating tumorigenesis and metastasis of ovarian cancer. YTHDF1 is frequently amplified in ovarian cancer and up-regulation of YTHDF1 is associated with the adverse prognosis of ovarian cancer patients. Furthermore, the protein but not the RNA abundance of EIF3C is increased in ovarian cancer and positively correlates with the protein expression of YTHDF1 in ovarian cancer patients, suggesting modification of EIF3C mRNA is more relevant to its role in cancer. Collectively, we identify the novel YTHDF1-EIF3C axis critical for ovarian cancer progression which can serve as a target to develop therapeutics for cancer treatment.

UNSTRUCTURED Abstract Purpose: To describe the clinical characteristics of Chinese patients with immunoglobulin light chain (AL) amyloidosis. Experimental Design: searches were made in MEDLINE, EMBASE, and CNKI. Articles (interventional and non-interventional) that reported Chinese patients with AL Amyloidosis were included in this study. The included characteristics were age, gender, λ type or κ type, body mass index (BMI), the time from onset of symptoms to diagnosis, Mayo cardiac staging, primary or secondary, organ involvement etc. Results: Sixty-seven articles reporting 5022 patients were included. The weighted average age of Chinese patients with AL amyloidosis was 57 years, and 61.2% of patients were males. 80.0%, 14.1% and 5.9% of patients were λ type, κ type and type unclear, respectively. The mean BMI was 22.82 ± 3.24 kg/m2. The time range from onset of symptoms to diagnosis was between 6 and 12 months. The proportion of patients at Mayo (2004) stage I, Ⅱ and Ⅲ was 24.6%, 34.3% and 41.1% (respectively). The proportion of patients at Mayo (2012) stage I, Ⅱ, Ⅲ and Ⅳ was 33.6%, 24.7%, 25.2% and 16.6% (respectively). 31.3% of patients were in New York Heart Association (NYHA) grade III-IV. 20.1% of patients were AL amyloidosis with concurrent multiple myeloma. 79.3% of patients were categorized as having more than one organ involvement. The involvement of the kidney, heart, skin/soft tissue and digestive system accounted for 84.3%, 62.5%, 41.5%, and 34.4% of patients, respectively. Conclusions: This scoping review suggests that most patients with AL amyloidosis were at an advanced stage when diagnosed in China. Epidemiological studies with a larger sample size are needed to comprehensively investigate the AL amyloidosis patients’ characteristics in the Chinese population.

METTL3 encodes the predominant catalytic enzyme to promote m

MicroRNA (miRNA) biogenesis is finely controlled by complex layers of post-transcriptional regulators, including RNA-binding proteins (RBPs). Here, we show that an RBP, QKI5, activates the processing of primary miR-124-1 (pri-124-1) during erythropoiesis. QKI5 recognizes a distal QKI response element and recruits Microprocessor through interaction with DGCR8. Furthermore, the recruited Microprocessor is brought to pri-124-1 stem loops by a spatial RNA-RNA interaction between two complementary sequences. Thus, mutations disrupting their base-pairing affect the strength of QKI5 activation. When erythropoiesis proceeds, the concomitant decrease of QKI5 releases Microprocessor from pri-124-1 and reduces mature miR-124 levels to facilitate erythrocyte maturation. Mechanistically, miR-124 targets TAL1 and c-MYB, two transcription factors involved in normal erythropoiesis. Importantly, this QKI5-mediated regulation also gives rise to a unique miRNA signature, which is required for erythroid differentiation. Taken together, these results demonstrate the pivotal role of QKI5 in primary miRNA processing during erythropoiesis and provide new insights into how a distal element on primary transcripts affects miRNA biogenesis.

Objective To investigate the effect of knockdown of YTH N

Alternative pre-mRNA splicing is a key mechanism for increasing proteomic diversity and modulating gene expression. Emerging evidence indicated that the splicing program is frequently dysregulated during tumorigenesis. Cancer cells produce protein isoforms that can promote growth and survival. The RNA-binding protein QKI5 is a critical regulator of alternative splicing in expanding lists of primary human tumors and tumor cell lines. However, its biological role and regulatory mechanism are poorly defined in gastric cancer (GC) development and progression. In this study, we demonstrated that the downregulation of QKI5 was associated with pTNM stage and pM state of GC patients. Re-introduction of QKI5 could inhibit GC cell proliferation, migration, and invasion in vitro and in vivo, which might be due to the altered splicing pattern of macroH2A1 pre-mRNA, leading to the accumulation of macroH2A1.1 isoform. Furthermore, QKI5 could inhibit cyclin L1 expression via promoting macroH2A1.1 production. Thus, this study identified a novel regulatory axis involved in gastric tumorigenesis and provided a new strategy for GC therapy.