KHSRP Stabilizes m6A-Modified Transcripts to Activate FAK Signaling and Promote Pancreatic Ductal Adenocarcinoma Progression
N 6-Methyladenosine (m6A) is the most prevalent RNA modification and is associated with various biological processes. Proteins that function as readers and writers of m6A modifications have been shown to play critical roles in human malignancies. Here, we identified KH-type splicing regulatory protein (KHSRP) as an m6A binding protein that contributes to the progression of pancreatic ductal adenocarcinoma (PDAC). High KHSRP levels were detected in PDAC and predicted poor patient survival. KHSRP deficiency suppressed PDAC growth and metastasis in vivo. Mechanistically, KHSRP recognized and stabilized FAK pathway mRNAs, including MET, ITGAV, and ITGB1, in an m6A-dependent manner, which led to activation of downstream FAK signaling that promoted PDAC progression. Targeting KHSRP with a PROTAC showed promising tumor suppressive effects in mouse models, leading to prolonged survival. Together, these findings indicate that KHSRP mediates FAK pathway activation in an m6A-dependent manner to support PDAC growth and metastasis, highlighting the potential of KHSRP as a therapeutic target in pancreatic cancer. Significance: KHSRP is a m6A-binding protein that stabilizes expression of FAK pathway mRNAs and that can be targeted to suppress FAK signaling and curb pancreatic ductal adenocarcinoma progression.
Authors
- Shaoqiu Liu (ORCID: https://orcid.org/0009-0002-5149-6045)
- Xiaowei He (ORCID: https://orcid.org/0000-0001-7910-6171)
- Rui Li (ORCID: https://orcid.org/0000-0003-0604-1770)
- Hongzhe Zhao (ORCID: https://orcid.org/0009-0005-9859-0452)
- Sihan Zhao (ORCID: https://orcid.org/0000-0002-1236-2274)
- Yifan Zhou (ORCID: https://orcid.org/0009-0000-9174-8169)
- Ji Liu (ORCID: https://orcid.org/0000-0002-9679-3716)
- Rufu Chen (ORCID: https://orcid.org/0009-0009-3479-8595)
- Lingxing Zeng (ORCID: https://orcid.org/0000-0002-0846-8762)
- Jian Zheng (ORCID: https://orcid.org/0000-0001-9831-7038)
- Quanbo Zhou (ORCID: https://orcid.org/0000-0001-9554-063X)
- Chunling Xue (ORCID: https://orcid.org/0009-0007-9616-004X)
- Ziming Chen (ORCID: https://orcid.org/0000-0001-5987-0148)
- Lisha Zhuang (ORCID: https://orcid.org/0009-0000-8177-3926)
- Ruihong Bai (ORCID: https://orcid.org/0009-0001-0050-9152)
- Mei Li (ORCID: https://orcid.org/0000-0002-9021-5886)
- Jialiang Zhang (ORCID: https://orcid.org/0000-0003-1626-6674)
- Dongxin Lin (ORCID: https://orcid.org/0000-0002-8723-8868)
- Zilan Xu (ORCID: https://orcid.org/0009-0006-0915-8076)
- Shaoping Zhang (ORCID: https://orcid.org/0000-0003-3364-7110)
- Xudong Huang (ORCID: https://orcid.org/0000-0002-5587-4448)
- Shuang Deng (ORCID: https://orcid.org/0009-0009-4025-0788)
Institutions
- Sun Yat-sen University (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- National Cancer Center (US)
- Sun Yat-sen Memorial Hospital (CN)
- Jiangsu Cancer Hospital (CN)
- Guangdong Academy of Medical Sciences (CN)
- Sun Yat-sen University Cancer Center (CN)
- Guangzhou Medical University Cancer Hospital (CN)
- Guangzhou Medical University (CN)
Publication Details
- Journal
- Cancer Research
- Published
- 2024-08-09
- DOI
- https://doi.org/10.1158/0008-5472.can-24-0927
- Citations
- 12
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 2.81
Funders
- National Natural Science Foundation of China
- National Key Research and Development Program of China