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

Permtermsin, Chalermsin; Lalchungnunga, H; Nakjang, Sirintra; Casement, John; Ogle, Laura Frances; Reeves, Helen L.; Strathdee, Gordon; Shukla, Ruchi

doi:10.3390/ijms24076387

Open AccessArticle

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

by

Chalermsin Permtermsin

¹,

H Lalchungnunga

¹,

Sirintra Nakjang

²,

John Casement

²,

Laura Frances Ogle

³,

Helen L. Reeves

^3,4

,

Gordon Strathdee

^1,* and

Ruchi Shukla

^1,5,*

¹

Biosciences Institute, Newcastle University Centre for Cancer, Newcastle University, Newcastle NE2 4HH, UK

²

Bioinformatics Support Unit, Newcastle University, Newcastle NE2 4HH, UK

³

Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Newcastle University, Newcastle NE2 4HH, UK

⁴

Liver Unit, Freeman Hospital, Newcastle-Upon-Tyne Hospitals NHS Foundation Trust, Newcastle-upon-Tyne NE7 7DN, UK

⁵

Department of Applied Sciences, Northumbria University, Newcastle NE1 8ST, UK

^*

Authors to whom correspondence should be addressed.

Int. J. Mol. Sci. 2023, 24(7), 6387; https://doi.org/10.3390/ijms24076387

Submission received: 31 January 2023 / Revised: 22 March 2023 / Accepted: 27 March 2023 / Published: 28 March 2023

(This article belongs to the Collection Feature Papers in Molecular Oncology)

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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.

Keywords: synthetic lethal gene; DNA methylation; HCC; TIAM1; RAC1

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MDPI and ACS Style

Permtermsin, C.; Lalchungnunga, H.; Nakjang, S.; Casement, J.; Ogle, L.F.; Reeves, H.L.; Strathdee, G.; Shukla, R. Identification of TIAM1 as a Potential Synthetic-Lethal-like Gene in a Defined Subset of Hepatocellular Carcinoma. Int. J. Mol. Sci. 2023, 24, 6387. https://doi.org/10.3390/ijms24076387

AMA Style

Permtermsin C, Lalchungnunga H, Nakjang S, Casement J, Ogle LF, Reeves HL, Strathdee G, Shukla R. Identification of TIAM1 as a Potential Synthetic-Lethal-like Gene in a Defined Subset of Hepatocellular Carcinoma. International Journal of Molecular Sciences. 2023; 24(7):6387. https://doi.org/10.3390/ijms24076387

Chicago/Turabian Style

Permtermsin, Chalermsin, H Lalchungnunga, Sirintra Nakjang, John Casement, Laura Frances Ogle, Helen L. Reeves, Gordon Strathdee, and Ruchi Shukla. 2023. "Identification of TIAM1 as a Potential Synthetic-Lethal-like Gene in a Defined Subset of Hepatocellular Carcinoma" International Journal of Molecular Sciences 24, no. 7: 6387. https://doi.org/10.3390/ijms24076387

APA Style

Permtermsin, C., Lalchungnunga, H., Nakjang, S., Casement, J., Ogle, L. F., Reeves, H. L., Strathdee, G., & Shukla, R. (2023). Identification of TIAM1 as a Potential Synthetic-Lethal-like Gene in a Defined Subset of Hepatocellular Carcinoma. International Journal of Molecular Sciences, 24(7), 6387. https://doi.org/10.3390/ijms24076387

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

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