Histone methyltransferase SETD2 modulates alternative splicing to inhibit intestinal tumorigenesis
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
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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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 3

Setd2 inactivation potentiates tumor malignance in an Apcmin/+ mice model.

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Setd2 inactivation potentiates tumor malignance in an Apcmin/+ mice mode...
(A and B) Western blot (A) and immunohistochemical staining (B) of the indicated proteins in small intestines of WT and Setd2ΔIEC mice. (C) H&E staining of representative Swiss roll of small intestines of 10-month-old mice. (D) Kaplan-Meier survival plots of Apcmin/+ and Apcmin/+; Setd2ΔIEC mice as indicated (n = 12) (log-rank test). (E) Macroscopic image, tumor number, and tumor load from the small intestines of 14-week-old mice as indicated (n = 12); 2-tailed Student’s t test. (F) Histogram showing the size distribution of tumors from 14-week-old mice as indicated (n = 11; χ2 test). (G and H) H&E images (G) and phospho-H3, cleaved caspase 3 staining (H) of the representative small intestines from 14-week-old Apcmin/+ and Apcmin/+; Setd2ΔIEC mice. Arrowhead denotes the discontinuous muscle layer due to the invasion of tumor cells. (I) Western blot of the indicated protein from small intestine lysates. Blot images are derived from replicate samples run on parallel gels. Scale bars: 50 μm (B, G, H, lower panel); 1 mm (C, G, upper panels); 1 cm (E).