PhD Scientific Days 2025

Poster Session I. - D: Pathological and Oncological Sciences

Reduced Histone Acetylation Associated with LKB1 Loss as a Potential Therapeutic Target in Lung Adenocarcinomas

Name of the presenter

Szalai Fatime

Institute/workplace of the presenter

Department of Pathology and Experimental Cancer Research

Authors

Fatime Szalai¹, Dániel Sztankovics¹, Dorottya Moldvai¹, Viktória Varga¹, Judit Moldvay^2,3, Judit Pápay¹, Anna Sebestyén¹, Ildikó Krencz¹

1: Department of Pathology and Experimental Cancer Research, Semmelweis University
2: I. Department of Pulmonology, National Korányi Institute of Pulmonology
3: Pulmonology Clinic, Szeged University, Albert Szent-Gyorgyi Medical School

Text of the abstract

Introduction
Loss-of-function mutations of the STK11 gene, encoding the LKB1 protein are observed in nearly one-third of lung adenocarcinomas (ADCs), which lead to AMPK inactivation and consequent mTOR hyperactivation. In addition to its inhibitory effects on tumorigenesis, AMPK may influence acetyl-CoA homeostasis, thereby affecting histone acetylation through the regulation of ACSS2 and ACLY. Furthermore, loss of LKB1 has also been associated with a decrease in innate immunity.
Methods
Immunohistochemical analysis of proteins related to the LKB1-AMPK-mTOR pathway, acetate and lipid metabolism, histone acetylation and immunoregulation was performed in lung ADC cases (N=100) and the correlation of protein expression with clinicopathological parameters was analysed. We also investigated the expression of proteins involved in antitumor immunity at the mRNA level in STK11 wild-type and mutant ADCs using the The Cancer Genome Atlas database. Finally, we determined the antiproliferative effects of mTOR and metabolic inhibitors in KRAS- and/or STK11-mutant lung ADC cell lines.
Results
Cases with no or low LKB1 expression had significantly lower levels of p-AMPK, p-ACC, ac-H3, ACSS2 and ACLY. In addition, the expression of PD-L1 and most tested mRNAs were also decreased in STK11 mutant cases. In our in vitro studies, we observed significantly decreased proliferation after rapamycin treatment in KRAS/STK11 mutant cell lines with high mTOR activity; furthermore, valproic acid and phenformin significantly potentiated the antitumor effect of rapamycin.
Conclusion
Our results show that histone acetylation is reduced in ADCs with LKB1 loss, which can be explained by potentially lower expression and nuclear translocation of ACSS2 and ACLY. Histone deacetylation inhibitors may be beneficial in the treatment of STK11-mutant ADCs, as they may restore the expression of certain tumor suppressors or proteins involved in antitumor immunity. Simultaneous inhibition of the mTOR signalling pathway and histone deacetylation may have significant antitumor effects, particularly in ADCs with high mTOR activity and STK11 mutation.
Funding:
2024-2.1.1-EKÖP-2024-00004 (F.S., D.M, D.S. V.V.), EFOP-3.6.3-VEKOP-16-2017-00009 (F.S., V.V.), TKP2021-EGA-24 (A.S.), NKFI-PD-146373 (I.K.), NKFI-K-142799 (A.S.), Hungarian Pulmonology Foundation (I.K.)