Metachronous liver metastases (MLM) are characterised by high incidence and high mortality in clinical colorectal cancer treatment. Currently traditional clinical methods cannot effectively predict and prevent the occurrence of metachronous liver metastasis in colorectal cancer. Based on 5hmC-Seal analysis of blood and tissue samples, this study found that portal venous blood was more relevant to tumour gDNA than peripheral blood. We performed a novel epigenetic liquid biopsy strategy using the 10 5hmC epigenetic alterations, to accurately distinguish MLM patients from patients without metastases. Among these epigenetic alterations, phosphodiesterase 4 (PDE4D) was highly increased in MLM patients and correlated with poor survival. Moreover, our studies demonstrated that PDE4D was a key metastasis-driven target for drug development. Interfering with the function of PDE4D significantly repressed liver metastases. Similarly, roflumilast, a PDE4 inhibitor for chronic obstructive pulmonary disease (COPD) therapy, also inhibits liver metastases. Further studies indicate that blocking the function of PDE4D can affect CRC invasion through the HIF-1α-CCN2 pathway. To develop a more efficient PDE4 inhibitor and reduce the occurrence of adverse events, we also designed several new compounds based on 2-arylbenzofurans and discovered lead L11 with potent affinity for PDE4D and significant suppression of liver metastases. In this work, our study provides a promising strategy for predicting metachronous liver metastasis and discovers L11 as a potential repurposed drug for inhibiting liver metastasis, which have the potential to benefit patients with CRC in the future.
Dear editor,
We are writing this letter to apply for an erratum of our published paper by Wu et al. We sincerely apologize for the mistakes and deeply regret any inconvenience this may have caused you.
Original version of Figure 5
The red block highlights the incorrect image of Vector control group.
The new version of Figure 5
A correct image of the vector control group (3 M) is included in Figure 5C.
The amended Figure 5
The reason for correction:
I recently discovered an error in Figure 5 while reviewing my paper. In the original version of Figure 5C, for 3 months after virus injection (upper panel), the image from Vector control group was inadvertently replaced by hTau group. Upon reviewing the original data, we realized that the mistake was made by inadvertently duplicated the layers during figure preparation. We have now included the correct image of Vector control group in the amended Figure 5. There were no significant differences in ChAT+ signals between the vector and overexpressing hTau groups (3 months). The experimental conclusions remain unchanged by this revision; therefore, no adjustments to the article's text are necessary.
Thank you for your consideration. We look forward to your kind response.
Sincerely yours,
Dr. Dongqin Wu
Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
Therapeutic options for advanced clear cell renal cell carcinoma (ccRCC) are currently inadequate. Earlier research has shown that the enzyme methyltransferase-like 14 (METTL14) can suppress ccRCC development through the modification of N6-methyladenosine (m6A). This study further explored its complex biological functions and underlying molecular mechanisms. Here, we identified zinc finger protein 14 (ZFP14) as a novel target of METTL14-mediated m6A, and its under-expression was associated with ccRCC tumourigenesis and progression. Detailed investigations revealed that METTL14 interacted directly with the 3′ untranslated region of ZFP14 mRNA, promoting m6A modification at two specific sites. These modifications were recognised by the protein insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2), which stabilised and enhanced the expression of ZFP14 mRNA. Functionally, the METTL14/ZFP14 axis suppressed in vitro growth, migration and invasiveness and in vivo proliferation and metastasis of ccRCC cells. ZFP14 potentially regulated numbers of transcripts, among which matrix metalloproteinase 1/3 (MMP1/3) were validated to be under-expressed by ZFP14. Crucially, ZFP14 interacted with the signal transducer and activator of transcription 3 (STAT3), augmenting its K48-linked ubiquitination and destabilising it via the proteasome pathway. Moreover, ZFP14 repressed ccRCC cell in vivo growth and metastasis as well as decreasing MMP1/3 levels by under-expressing STAT3. These observations confirmed that ZFP14 served as both a novel target for METTL14-mediated m6A modification and a significant tumour suppressor in ccRCC, shedding light on the cellular and molecular operations in ccRCC and opening up possibilities for novel therapeutic strategies.
ZFP14 under-expression is associated with ccRCC tumourigenesis and progression.
METTL14-mediated m6A enhances ZFP14 mRNA stability and expression with IGF2BP2 as the reader in ccRCC.
ZFP14 promotes the degradation of STAT3 by enhancing its K48-linked ubiquitination, inhibiting ccRCC progression.
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