2. Academic Validation
  3. Phospholipase C delta 1 inhibits WNT/β-catenin and EGFR-FAK-ERK signaling and is disrupted by promoter CpG methylation in renal cell carcinoma

Phospholipase C delta 1 inhibits WNT/β-catenin and EGFR-FAK-ERK signaling and is disrupted by promoter CpG methylation in renal cell carcinoma

  • Clin Epigenetics. 2023 Feb 27;15(1):30. doi: 10.1186/s13148-023-01448-2.
Jianlian Xie # 1,  Jun Zhou # 2 3,  Jiliang Xia 2,  Ying Zeng 2,  Guo Huang 2,  Weihong Zeng 2,  Tingyu Fan 2,  Lili Li 1,  Xi Zeng 4,  Qian Tao 5
Affiliations

Affiliations

  • 1 Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Translational Oncology, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.
  • 2 Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.
  • 3 Department of Burn and Plastic Surgery, General Hospital of Southern Theater Command, PLA, Guangzhou, China.
  • 4 Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China. xzeng@usc.edu.cn.
  • 5 Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Translational Oncology, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China. qtao@cuhk.edu.hk.
  • # Contributed equally.
PMID: 36849889 DOI: 10.1186/s13148-023-01448-2
Abstract

Background: PLCD1, located at 3p22, encodes an Enzyme that mediates cellular metabolism and homeostasis, intracellular signal transduction and movement. PLCD1 plays a pivotal role in tumor suppression of several types of cancers; however, its expression and underlying molecular mechanisms in renal cell carcinoma (RCC) pathogenesis remain elusive.

Methods: RT-PCR and Western blot were used to detect PLCD1 expression in RCC cell lines and normal tissues. Bisulfite treatment, MSP and BGS were utilized to explore the CpG methylation status of PLCD1 promoter. Online databases were analyzed for the association between PLCD1 expression/methylation and patient survival. In vitro experiments including CCK8, colony formation, wound-healing, transwell migration and invasion, immunofluorescence and flow cytometry assays were performed to evaluate tumor cell behavior. Luciferase assay and Western blot were used to examine effect of PLCD1 on Wnt/β-catenin and EGFR-FAK-ERK signaling.

Results: We found that PLCD1 was widely expressed in multiple adult normal tissues including kidney, but frequently downregulated or silenced in RCC due to its promoter CpG methylation. Restoration of PLCD1 expression inhibited the viability, migration and induced G2/M cell cycle arrest and Apoptosis in RCC cells. PLCD1 restoration led to the inhibition of signaling activation of Wnt/β-catenin and EGFR-FAK-ERK pathways, and the EMT program of RCC cells.

Conclusions: Our results demonstrate that PLCD1 is a potent tumor suppressor frequently inactivated by promoter methylation in RCC and exerts its tumor suppressive functions via suppressing Wnt/β-catenin and EGFR-FAK-ERK signaling. These findings establish PLCD1 as a promising prognostic biomarker and treatment target for RCC.

Keywords

CpG methylation; EMT; PLCD1; RCC; WNT/β-catenin.

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