Histone methyltransferase SETD2 modulates alternative splicing to inhibit intestinal tumorigenesis
Huairui Yuan, … , Qintong Li, Jun Qin
Huairui Yuan, … , Qintong Li, Jun Qin
Published September 1, 2017; First published August 21, 2017
Citation Information: J Clin Invest. 2017;127(9):3375-3391. https://doi.org/10.1172/JCI94292.
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Research Article Oncology

Histone methyltransferase SETD2 modulates alternative splicing to inhibit intestinal tumorigenesis

Abstract

The histone H3K36 methyltransferase SETD2 is frequently mutated or deleted in a variety of human tumors. Nevertheless, the role of SETD2 loss in oncogenesis remains largely undefined. Here, we found that SETD2 counteracts Wnt signaling and its inactivation promotes intestinal tumorigenesis in mouse models of colorectal cancer (CRC). SETD2 was not required for intestinal homeostasis under steady state; however, upon irradiation, genetic inactivation of Setd2 in mouse intestinal epithelium facilitated the self-renewal of intestinal stem/progenitor cells as well as tissue regeneration. Furthermore, depletion of SETD2 enhanced the susceptibility to tumorigenesis in the context of dysregulated Wnt signaling. Mechanistic characterizations indicated that SETD2 downregulation affects the alternative splicing of a subset of genes implicated in tumorigenesis. Importantly, we uncovered that SETD2 ablation reduces intron retention of dishevelled segment polarity protein 2 (DVL2) pre-mRNA, which would otherwise be degraded by nonsense-mediated decay, thereby augmenting Wnt signaling. The signaling cascades mediated by SETD2 were further substantiated by a CRC patient cohort analysis. Together, our studies highlight SETD2 as an integral regulator of Wnt signaling through epigenetic regulation of RNA processing during tissue regeneration and tumorigenesis.

Authors

Huairui Yuan, Ni Li, Da Fu, Jiale Ren, Jingyi Hui, Junjie Peng, Yongfeng Liu, Tong Qiu, Min Jiang, Qiang Pan, Ying Han, Xiaoming Wang, Qintong Li, Jun Qin

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Figure 1

Clinical relevance of SETD2 expression in human CRC.

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Clinical relevance of SETD2 expression in human CRC. (A) SETD2 mRNA leve...
(A) SETD2 mRNA levels in 30 matched tumor and paracarcinoma tissues (paired t test, P = 0.0035). (B) SETD2 and H3K36me3 protein levels in 6 pairs of random CRC samples. Blot images are derived from replicate samples run on parallel gels. N, adjacent normal specimens; T, matched tumor tissues. (C) Expression of SETD2 was assessed in tissue microarray. SETD2 staining indexes using a 10-point quantification scale in normal colon counterparts (n = 35) and tumors (n = 149) are shown (χ2 test, P = 0.0015). (D) Boxed plot of SETD2 expression assessed by blinded IHC analyses of TMA at different clinical stages (Kruskal-Wallis test). (E) Kaplan-Meier plot of overall survival and metastasis-free survival of patients based on SETD2 expression levels. A log-rank test was used for statistical analysis. (F) Kaplan-Meier survival curves for disease relapse–free stratified by SETD2 expression levels using GEO data sets GSE35982 and GSE17538 (P values by log-rank test). Scale bars: 50 μm.