PDE4DIP contributes to colorectal cancer growth and chemoresistance through modulation of the NF1/RAS signaling axis

Sep 24, 2026

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PDE4DIP (phosphodiesterase 4D interacting protein) is a centrosome/Golgi-associated factor frequently altered in cancers, yet its function in human colorectal cancer has been unclear. This study identifies an oncogenic role for PDE4DIP in CRC growth and adaptive MEK inhibitor resistance. PDE4DIP is upregulated in CRC tissues, correlating with clinicopathological features and poor patient prognosis. PDE4DIP knockdown suppresses KRAS-mutant CRC growth by inhibiting RAS signaling, promoting NF1 degradation via PLCγ/PKCε recruitment to the Golgi. Elevated PDE4DIP drives adaptive MEKi resistance by reactivating RAS/ERK, supporting PDE4DIP targeting as a therapeutic strategy.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages13

Reading Time33 min

AccessFree to download

Introduction

Clinical background of colorectal cancer and KRAS-driven disease

Known roles of PDE4DIP and rationale for study

Results

PDE4DIP is upregulated in colorectal cancer tissues

PDE4DIP function in CRC growth and RAS signaling

Mechanism linking PDE4DIP to NF1 degradation and adaptive MEKi resistance

Conclusion

[www.nature.com/cddis](www.nature.com/cddis) ARTICLE OPEN PDE4DIP contributes to colorectal cancer growth and chemoresistance through modulation of the NF1/RAS signaling axis Rulu Pan1,5, Juji Dai2,5, Weicheng Liang1, Hongxiao Wang 1, Lin Ye1, Siqi Ye1, Ziqi Lin 1, Shishun Huang 1, Yan Xiong 1, Li Zhang 1, Liting Lu 1, Ouchen Wang3, Xian Shen4, Wanqin Liao 1 ✉ and Xincheng Lu 1 ✉ © The Author(s) 2023 | | | | | --- | --- | --- | | | Phosphodiesterase 4D interacting protein (PDE4DIP) is a centrosome/Golgi protein associated with cyclic nucleotide phosphodiesterases. PDE4DIP is commonly mutated in human cancers, and its alteration in mice leads to a predisposition to intestinal cancer. However, the biological function of PDE4DIP in human cancer remains obscure. Here, we report for the ﬁrst time the oncogenic role of PDE4DIP in colorectal cancer (CRC) growth and adaptive MEK inhibitor (MEKi) resistance. We show that the expression of PDE4DIP is upregulated in CRC tissues and associated with the clinical characteristics and poor prognosis of CRC patients. Knockdown of PDE4DIP impairs the growth of KRAS-mutant CRC cells by inhibiting the core RAS signaling pathway. PDE4DIP plays an essential role in the full activation of oncogenic RAS/ERK signaling by suppressing the expression of the RASGTPase-activating protein (RasGAP) neuroﬁbromin (NF1) . Mechanistically, PDE4DIP promotes the recruitment of PLCγ/PKCε to the Golgi apparatus, leading to constitutive activation of PKCε, which triggers the degradation of NF1 . Upregulation of PDE4DIP results in adaptive MEKi resistance in KRAS-mutant CRC by reactivating the RAS/ERK pathway. Our work reveals a novel functional link between PDE4DIP and NF1/RAS signal transduction and suggests that targeting PDE4DIP is a promising therapeutic strategy for | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | KRAS-mutant CRC. | | | | | Cell Death and Disease (2023)14:373; [https://doi.org/10.1038/s41419-023-05885-y](https://doi.org/10.1038/s41419-023-05885-y) | | | | | | INTRODUCTION Colorectal cancer (CRC) is the third most common cancer worldwide, with approximately two million patients newly diagnosed with CRC annually [1]. CRC carcinogenesis is a multistep process resulting from the accumulation of genetic mutations and epigenetic modiﬁcations in colonic mucosal cells, ultimately leading to the initiation and malignant progression of CRC [2] . KRAS is the most commonly mutated oncogene in colon cancer patients, and there are no clinically proven strategies for the treatment of KRAS-driven CRC [3, 4] . Therefore, a more complete understanding of the regulation of this key gene will contribute to the clinical treatment of CRC. Phosphodiesterase 4D interacting protein (PDE4DIP) is a CDK5RAP2 paralog in vertebrates [5] . In a yeast two-hybrid screen, PDE4DIP was identiﬁed as an interactor of phosphodiesterase 4D (PDE4D), an enzyme controlling the cAMP level [6] . With several transcript variants encoding different isoforms, PDE4DIP is ubiquitously expressed in mammalian cells, but its biological functions remain largely unknown [5–7] . PDE4DIP has been reported to play an important role in the regulation of cardiac contractility by affecting the phosphorylation of cMyBPC [8] . Two other studies showed that PDE4DIP variants are associated with an increased risk for ischemic stroke and that defects in this gene may be a cause of myeloproliferative disorders (MPDs) [9, 10] . In mammalian cells, PDE4DIP localizes to the centrosome and Golgi apparatus and binds directly to AKAP9, EB1/EB3, and FAM161A to form a functional complex [11–13] . Disrupting PDE4DIP expression affects endoplasmic reticulum (ER)-to-Golgi trafﬁcking, Golgi/ centrosome organization, and microtubule assembly [5, 6, 11] . Recently, accumulating evidence has implied that the PDE4DIP gene is associated with cancer risk [7] . For example,

FAQs

What role does PDE4DIP play in colorectal cancer growth?

PDE4DIP promotes CRC growth, with its expression upregulated in CRC tissues and linked to poor outcomes. Knockdown of PDE4DIP impairs the growth of KRAS-mutant CRC cells by inhibiting core RAS signaling.

How does PDE4DIP influence MEK inhibitor resistance in KRAS-mutant CRC?

Upregulation of PDE4DIP results in adaptive MEK inhibitor resistance. It restores RAS/ERK pathway activity, counteracting the effect of MEK inhibition.

What mechanism connects PDE4DIP to NF1/RAS signal transduction?

PDE4DIP recruits PLCγ/PKCε to the Golgi, causing constitutive activation of PKCε. This triggers degradation of NF1, thereby enabling full activation of oncogenic RAS/ERK signaling.

Sep 24, 2026

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