PHF5A promotes colorectal cancerprogression by alternative splicing of TEAD2

Yue Chang; Yulu Zhao; Liya Wang; Meijuan Wu; Chenglong He; Mengxi Huang; Zengjie Lei; Jiahe Yang; Siqi Han; Bibo Wang; Yanyan Chen; Chao Liu; Hongju Yu; Lijun Xue; Jian Geng; Yanan Chen; Tingting Dai; Lili Ren; Qian Wang; Xiaobei Liu; Xiaoyuan Chu; Cheng Chen

doi:10.1016/j.omtn.2021.10.025

PHF5A promotes colorectal cancerprogression by alternative splicing of TEAD2

Mol Ther Nucleic Acids. 2021 Nov 3:26:1215-1227. doi: 10.1016/j.omtn.2021.10.025. eCollection 2021 Dec 3.

Authors

Yue Chang¹, Yulu Zhao², Liya Wang³, Meijuan Wu¹, Chenglong He⁴, Mengxi Huang¹, Zengjie Lei¹, Jiahe Yang¹, Siqi Han⁴, Bibo Wang¹, Yanyan Chen¹, Chao Liu³, Hongju Yu¹, Lijun Xue¹, Jian Geng¹, Yanan Chen¹, Tingting Dai¹, Lili Ren¹, Qian Wang¹, Xiaobei Liu¹, Xiaoyuan Chu^{1

2

4}, Cheng Chen^{1

2

4}

Affiliations

¹ Department of Medical Oncology, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, China.
² Department of Medical Oncology, Jinling Hospital, Nanjing Medical University, Nanjing 210002, China.
³ Clinical Medical College, Yangzhou University, Yangzhou 225009, China.
⁴ Department of Medical Oncology, Jinling Hospital, First School of Clinical Medicine, Southern Medical University, Nanjing 210002, China.

Abstract

Dysregulated alternative splicing (AS) plays critical roles in driving cancer progression, and the underlying mechanisms remain largely unknown. Here, we demonstrated that PHF5A, a component of U2 small nuclear ribonucleoproteins, was frequently upregulated in colorectal cancer (CRC) samples and associated with poor prognosis. PHF5A promoted proliferation and metastasis of CRC cells in vitro and in vivo. Transcriptomic analysis identified PHF5A-regulated AS targets and pathways. Particularly, PHF5A induced TEAD2 exon 2 inclusion to activate YAP signaling, and interference of TEAD2-L partially reversed the PHF5A-mediated tumor progression. Pharmacological inhibition of PHF5A using pladienolide B had potent antitumor activity. Collectively, these data revealed the oncogenic role of PHF5A in CRC through regulating AS and established PHF5A as potential therapeutic target.

Keywords: PHF5A; TEAD2; alternative splicing; colorectal cancer; therapeutic target.