RNA binding protein DDX3X drives pancreatic cancer progression via the TLE2-MYL9 axis

Authors:

Yuanyang Wang, Qianyi Yang, Feng Lin, Xiaowei Song, Gang Yang, Dahan Wen, Yingyun Yang, Bicheng Wu, Yunmeng Meng, Ning, Xiaomei Lu, Chunyang Xiong, Wen Zhao, Junbo Liang, Taiping Zhang, Yuying Liu

Keywords:

pancreatic ductal adenocarcinoma; PDAC; RNA binding protein; DDX3X; pancreatic cancer; TLE2-MYL9; DEAD-box helicase 3X-linked; oncogene;

Abstract:

Current treatments for pancreatic ductal adenocarcinoma (PDAC) fall short of meeting clinical needs, highlighting the urgent need for a comprehensive understanding of PDAC progression, which involves not only biochemical signals but also essential biomechanical cues. Here, we used a CRISPR-Cas9 screen in an orthotopic xenograft model to explore PDAC dynamics. The RNA binding protein DEAD-box helicase 3X-linked (DDX3X) was identified as a pivotal oncogene and biomechanical checkpoint. Specifically, DDX3X up-regulation in PDAC promoted tumorigenesis and metastasis, primarily through the transcriptional repressor TLE family member 2 (TLE2). Dysregulation of DDX3X in the tumor destabilized TLE2 messenger RNA and therefore disrupted the interaction with KLF4 (KLF transcription factor 4), leading to increased expression of myosin light chain 9 (MYL9). This change remodeled F-actin, enhancing tumor cell traction forces and consequently facilitating tumor metastasis. Targeting the DDX3X-TLE2-MYL9 pathway considerably reduces PDAC progression. This research reveals a promising approach for treating PDAC by focusing on biomechanical cues.

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