PRPF19 facilitates colorectal cancer liver metastasis through activation of the Src-YAP1 pathway via K63-linked ubiquitination of MYL9

Sep 24, 2026

Distant metastasis is a major cause of colorectal cancer (CRC) mortality, yet the mechanisms driving liver spread remain insufficiently defined. This study identifies the E3 ubiquitin ligase PRPF19 as positively associated with liver metastasis and worse clinical outcomes in CRC. Functional assays show PRPF19 enhances CRC cell migration and invasion. Mechanistically, PRPF19 stabilizes MYL9 through K63-linked ubiquitination and activates a Src–YAP1 cascade, indicating the PRPF19/MYL9 axis as a potential therapeutic strategy for CRC.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages14

Reading Time35 min

AccessFree to download

Introduction

PRPF19 and ubiquitin ligases in CRC

MYL9, actomyosin, and metastasis

Hippo pathway and YAP1 activation

Results

PRPF19 is upregulated in CRC

[www.nature.com/cddis](www.nature.com/cddis) ARTICLE OPEN PRPF19 facilitates colorectal cancer liver metastasis through activation of the Src-YAP1 pathway via K63-linked ubiquitination of MYL9 Rui Zhou 1,3, Jie Chen1,3, Yunxiuxiu Xu1, Yibiao Ye1, Guoping Zhong 1, Tao Chen 1 ✉ and Lin Qiu 2 ✉ © The Author(s) 2023 | | | | | --- | --- | --- | | | Distant metastasis is one of the leading causes of cancer-related mortality of colorectal cancer (CRC) . Dysregulation of E3 ubiquitin ligases has been implicated in acting vital roles in multiple cancers. In this study, we found that the E3 ubiquitin ligase, PRPF19 was positively correlated with liver metastasis, and predicted a worse clinical outcome in CRC. However, the biological effects and the underlying molecular mechanisms of PRPF19 in CRC remain elusive thus far. We illustrated that PRPF19 promoted the migration and invasion capability of CRC cells in both gain-and loss-of function assays. Mechanistically, we uncovered that myosin light chain 9 (MYL9) was the downstream substrate of PRPF19 . PRPF19 enhanced the stability of MYL9 via K63-linked ubiquitination, and promoted the migration and invasion capability of CRC cells in an MYL9-mediated manner. Furthermore, the Src–YAP1 cascade wasidentiﬁed as the downstream effector mechanism by which the PRPF19/MYL9 axis promoted metastasis in CRC. Taken together, our ﬁndings highlighted that the PRPF19/MYL9 axis served as a novel mechanism in CRC metastasis, which provided an attractive | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | therapeutic strategy for CRC treatment. | | | | | Cell Death and Disease (2023)14:258; [https://doi.org/10.1038/s41419-023-05776-2](https://doi.org/10.1038/s41419-023-05776-2) | | | | | | INTRODUCTION Colorectal cancer (CRC) is the third most common type of cancer worldwide, and distant metastasis remains one of the most critical causes of cancer-associated mortality of CRC. The most common metastasis site of CRC is the liver, and nearly 50% of patients with late-stage CRC develop liver metastasis [1, 2] . Therefore, considerable efforts have been concentrated on the relevant mechanisms concerning metastasis of CRC, and searching for novel biomarkers which contribute to improving the outcome of patients with distant metastasis is still an enormous challenge in cancer research. E3 ubiquitin ligases (E3s) were involved in a variety of cellular processes ranging from protein degradation to modulating protein-protein interactions, from activating to inactivating substrates, and dysregulation of E3s often contributes to cancer development [3–6] . Accumulating evidence revealed that degradation of oncoproteins may contribute to countering the almost inevitable drug resistance due to target inhibition, and increase the peptide presentation capability of MHC molecules which synergize with cancer immunotherapy [5, 7], implying that targeting E3s may provide a promising access for therapeutic intervention of cancer. Pre-mRNA processing factor 19 (PRPF19) isan E3 ligase, involved in regulating cell damage repair [8], inhibits cell cycle arrest and prolongs cell survival in vitro [9, 10] . It is worth mentioning that the expression of PRPF19 is increased in the liver metastasis tumor tissues of CRC in a large-scale proteogenomics study [11], which drew our attention to evaluate the biological behavior of PRPF19 in CRC. As an E3 ligase, the downstream target substrates of PRPF19 are still not well characterized. Myosin is an actin-dependent molecular motor, which moves along actin ﬁlaments and generates mechanical forces within cells, which are transmitted to the extracellular matrix (ECM) through integrin-mediated cell-ECM adhesions, and subsequently lead to ECM remodeling to adapt to changes in mechanical forces [12] . As one component of the actomyosin contractile apparatus, myosin light chain 9 (MYL9) regulates muscle contraction, ECM stiff

FAQs

What role does PRPF19 play in colorectal cancer liver metastasis?

PRPF19 is positively correlated with liver metastasis and predicts a worse clinical outcome in CRC. It promotes CRC cell migration and invasion, supporting a functional role in metastasis.

How does PRPF19 regulate MYL9?

PRPF19 enhances the stability of MYL9 via K63-linked ubiquitination. MYL9 then mediates the pro-migratory and pro-invasive effects in CRC cells.

Which signaling pathway links PRPF19/MYL9 to metastasis?

The study identifies the Src–YAP1 cascade as the downstream effector mechanism activated by the PRPF19/MYL9 axis, promoting metastasis in CRC.

Sep 24, 2026

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