HORMAD1 Is a Negative Prognostic Indicator in Lung Adenocarcinoma and Specifies Resistance to Oxidative and Genotoxic Stress

Abstract

Cancer testis antigens (CTA) are expressed in testis and placenta and anomalously activated in a variety of tumors. The mechanistic contribution of CTAs to neoplastic phenotypes remains largely unknown. Using a chemigenomics approach, we find that the CTA HORMAD1 correlates with resistance to the mitochondrial complex I inhibitor piericidin A in non-small cell lung cancer (NSCLC). Resistance was due to a reductive intracellular environment that attenuated the accumulation of free radicals. In human lung adenocarcinoma (LUAD) tumors, patients expressing high HORMAD1 exhibited elevated mutational burden and reduced survival. HORMAD1 tumors were enriched for genes essential for homologous recombination (HR), and HORMAD1 promoted RAD51-filament formation, but not DNA resection, during HR. Accordingly, HORMAD1 loss enhanced sensitivity to γ-irradiation and PARP inhibition, and HORMAD1 depletion significantly reduced tumor growth These results suggest that HORMAD1 expression specifies a novel subtype of LUAD, which has adapted to mitigate DNA damage. In this setting, HORMAD1 could represent a direct target for intervention to enhance sensitivity to DNA-damaging agents or as an immunotherapeutic target in patients. This study uses a chemigenomics approach to demonstrate that anomalous expression of the CTA HORMAD1 specifies resistance to oxidative stress and promotes HR to support tumor cell survival in NSCLC. .

Protein Oxidative Damage in UV-Related Skin Cancer and Dysplastic Lesions Contributes to Neoplastic Promotion and Progression

“…Nonetheless, these data are supported by the lack of significant identifications in the comparison between L and NPE, which sustain a decrease of protein oxidation in L areas compared to PL areas to levels similar to NPE regions. Consistently, similar findings have been reported about the cervical cancer vs. high-grade cervical dysplastic lesions [10] and an increased antioxidant response has been reported to account for an increased cell resistance to genotoxic and oxidative distress in a subset of Lung adenocarcinomas [61] and the hypothesis has been proposed that an adaptive selection of best fitting clones to the sharply pro-oxidant neoplastic environment takes places along with tumour progression. However, extreme caution is required in interpreting the reduced carbonylation level of a set of proteins within the context of the extensively deranged metabolisms of neoplastic cells.…”

Weighted Gene Coexpression Network Analysis of Features That Control Cancer Stem Cells Reveals Prognostic Biomarkers in Lung Adenocarcinoma

“…Sanada et al (2019) evaluated the miR-143-5p molecular network in LUAD using whole-genome sequencing combined with miRNA database analysis and identified 11 prognostic target genes, including RAD51. Another study showed that the abnormal expression of other genes, such as cancer testis antigen (CTA), can also promote RAD51 filament formation and simultaneously enhance the sensitivity to DNA damaging agents (Nichols et al, 2018). Dong et al (2019) revealed that RAD51 plays an important role in radiation reactions.…”

Aberrantly expressed HORMAD1 disrupts nuclear localization of MCM8–MCM9 complex and compromises DNA mismatch repair in cancer cells

“…Cancer/testis antigens are a group of proteins that are specifically expressed in testis but are aberrantly expressed in cancers. Later studies have confirmed that HORMAD1 is aberrantly expressed in several cancers, including gastric cancers 7 , lung cancers 8 , 9 , basal type and triple-negative breast cancers 10 – 14 , and ovarian cancers 15 . Aberrant HORMAD1 expression is caused by promoter hypomethylation 8 , 13 , 14 , which is believed to be unselected due to genome-wide loss of DNA methylation in many cancers 16 .…”