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Updated: Jun 26, 2026
Discovery of Driver Genes in Colorectal HT29-derived Cancer Stem-Like Tumorspheres
Published on: July 22, 2020
Genomics screen in transformed stem cells reveals RNASEH2A, PPAP2C, and ADARB1 as putative anticancer drug targets
James M Flanagan1, Juan M Funes, Stephen Henderson
1Cancer Research UK Viral Oncology Group, University College London Cancer Institute, Paul O'Gorman Building, 74 Huntley Street, London, United Kingdom WC1E 6BT. j.flanagan@ucl.ac.uk
Abstract:
Since the sequencing of the human genome, recent efforts in cancer drug target discovery have focused more on the identification of novel functions of known genes and the development of more appropriate tumor models. In the present study, we investigated in vitro transformed human adult mesenchymal stem cells (MSC) to identify novel candidate cancer drug targets by analyzing the transcriptional profile of known enzymes compared with non-transformed MSC. The identified enzymes were compared with published cancer gene expression data sets. Surprisingly, the majority of up-regulated enzymes are already known cancer drug targets or act within known druggable pathways. Only three enzymes (RNASEH2A, ADARB1, and PPAP2C) are potentially novel targets that are up-regulated in transformed MSC and expressed in numerous carcinomas and sarcomas. We confirmed the overexpression of RNASEH2A, PPAP2C, and ADARB1 in transformed MSC, transformed fibroblasts, and cancer cell lines MCF7, SK-LMS1, MG63, and U2OS. In functional assays, we show that small interfering RNA knockdown of RNASEH2A inhibits anchorage-independent growth but does not alter in vitro proliferation of cancer cell lines, normal MSC, or normal fibroblasts. Knockdown of PPAP2C impaired anchorage-dependent in vitro growth of cancer cell lines and impaired the in vitro growth of primary MSC but not differentiated human fibroblasts. We show that the knockdown of PPAP2C decreases cell proliferation by delaying entry into S phase of the cell cycle and is transcriptionally regulated by p53. These in vitro data validate PPAP2C and RNASEH2A as putative cancer targets and endorse this in silico approach for identifying novel candidates.
Insights
Researchers identified novel cancer drug targets by analyzing enzyme expression in transformed stem cells. RNASEH2A and PPAP2C show promise as new therapeutic targets, impacting cancer cell growth and proliferation.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Cancer drug target discovery increasingly relies on understanding gene function and utilizing advanced tumor models.
- Identifying novel enzymes with altered expression in cancer is crucial for developing new therapeutic strategies.
Purpose of the Study:
- To identify novel cancer drug targets by analyzing the transcriptional profile of enzymes in in vitro transformed human mesenchymal stem cells (MSC) compared to non-transformed MSC.
- To validate potential novel targets by comparing their expression with existing cancer gene datasets and confirming overexpression in cancer cell lines.
Main Methods:
- Transcriptional profiling of enzymes in transformed versus non-transformed human adult mesenchymal stem cells (MSC).
- In silico comparison of identified enzymes with public cancer gene expression datasets.
- Experimental validation of enzyme overexpression in various cancer cell lines and transformed cells.
- Functional assays using small interfering RNA (siRNA) to assess the impact of target knockdown on cancer cell growth and proliferation.
Main Results:
- Most up-regulated enzymes in transformed MSC were already known cancer drug targets or involved in known druggable pathways.
- Three enzymes—RNASEH2A, ADARB1, and PPAP2C—were identified as potentially novel targets, overexpressed in transformed MSC and present in multiple carcinomas and sarcomas.
- RNASEH2A knockdown inhibited anchorage-independent growth of cancer cells.
- PPAP2C knockdown impaired anchorage-dependent growth of cancer cells and in vitro growth of primary MSC, delaying cell cycle progression into S phase.
Conclusions:
- PPAP2C and RNASEH2A are validated as putative cancer targets based on in vitro functional data.
- The in silico approach of analyzing transcriptional profiles in transformed stem cells is effective for identifying novel cancer drug candidates.
- Further investigation into RNASEH2A and PPAP2C could lead to the development of new cancer therapies.
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