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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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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.