Identification of TIAM1 as a Potential Synthetic-Lethal-like Gene in a Defined Subset of Hepatocellular Carcinoma

Chalermsin Permtermsin, H. Lalchungnunga, Sirintra Nakjang, John Casement, Laura Frances Ogle, Helen L. Reeves, Gordon Strathdee*, Ruchi Shukla*, Michael Welsh (Editor)

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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Abstract

Hepatocellular carcinoma (HCC), the most common type of liver cancer, has very poor outcomes. Current therapies often have low efficacy and significant toxicities. Thus, there is a critical need for the development of novel therapeutic approaches for HCC. We have developed a novel bioinformatics pipeline, which integrates genome-wide DNA methylation and gene expression data, to identify genes required for the survival of specific molecular cancer subgroups but not normal cells. Targeting these genes may induce cancer-specific “synthetic lethality”. Initially, five potential HCC molecular subgroups were identified based on global DNA methylation patterns. Subgroup-2 exhibited the most unique methylation profile and two candidate subtype-specific vulnerability or SL-like genes were identified for this subgroup, including TIAM1, a guanine nucleotide exchange factor encoding gene known to activate Rac1 signalling. siRNA targeting TIAM1 inhibited cell proliferation in TIAM1-positive (subgroup-2) HCC cell lines but had no effect on the normal hepatocyte HHL5 cell line. Furthermore, TIAM1-positive/subgroup-2 cell lines were significantly more sensitive to the TIAM1/RAC1 inhibitor NSC23766 compared with TIAM1-negative HCC lines or the normal HHL5 cell line. The results are consistent with a synthetic lethal role for TIAM1 in a methylation-defined HCC subgroup and suggest it may be a viable therapeutic target in this subset of HCC patients.
Original languageEnglish
Article number6387
Pages (from-to)1-13
Number of pages13
JournalInternational Journal of Molecular Sciences
Volume24
Issue number7
DOIs
Publication statusPublished - 28 Mar 2023

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