The HER2-positive subtype accounts for approximately one-fifth of all breast cancers. Insensitivity and development of acquired resistance to targeted therapies in some patients contribute to their poor prognosis. HER2 overexpression is associated with metabolic reprogramming, facilitating cancer cell growth and survival. Novel liver X receptor (LXR) ligand GAC0001E5 (1E5) has been shown to inhibit cancer cell proliferation by disrupting glutaminolysis and inducing oxidative stress. In this study, HER2-positive breast cancer cells were treated with 1E5 to determine their potential inhibitory effects and mechanisms of action in HER2-positive breast cancers. Similar to previous observations in other cancer types, 1E5 treatments inhibited LXR activity, expression, and cancer cell proliferation. Expression of fatty acid synthesis genes, including fatty acid synthase (FASN), was downregulated following 1E5 treatment, and results from co-treatment experiments with an FASN inhibitor suggest that the same pathway is targeted by 1E5. Treatments with 1E5 disrupted glutaminolysis and resulted in increased oxidative stress. Strikingly, HER2 transcript and protein levels were both significantly downregulated by 1E5. Taken together, these findings indicate the therapeutic potential of targeting HER2 overexpression and associated metabolic reprogramming via the modulation of LXR in HER2-positive breast cancers.

Antiandrogen is part of the standard-of-care treatment option for metastatic prostate cancer. However, prostate cancers frequently relapse, and the underlying resistance mechanism remains incompletely understood. This study seeks to investigate whether long non-coding RNAs (lncRNAs) contribute to the resistance against the latest antiandrogen drug, darolutamide. Our RNA sequencing analysis revealed significant overexpression of LOC730101 in darolutamide-resistant cancer cells compared to the parental cells. Elevated LOC730101 levels were also observed in clinical samples of metastatic castration-resistant prostate cancer (CRPC) compared to primary prostate cancer samples. Silencing LOC730101 with siRNA significantly impaired the growth of darolutamide-resistant cells. Additional RNA sequencing analysis identified a set of genes regulated by LOC730101, including key players in the cell cycle regulatory pathway. We further demonstrated that LOC730101 promotes darolutamide resistance by competitively inhibiting microRNA miR-1-3p. Moreover, by Hi-C sequencing, we found that LOC730101 is located in a topologically associating domain (TAD) that undergoes specific gene induction in darolutamide-resistant cells. Collectively, our study demonstrates the crucial role of the lncRNA LOC730101 in darolutamide resistance and its potential as a target for overcoming antiandrogen resistance in CRPC.

Traditional ChIP-seq analysis is essential for identifying transcription factor (TF) binding sites, but it is constrained by its linear view of the genome. How TF-bound regions interact with distant genomic loci within the three-dimensional (3D) chromatin architecture often remains unclear, limiting our ability to interpret enhancer-promoter communication and long-range gene regulation. To address these limitations, we developed ChIP-SP, an R package that integrates ChIP-seq data with Hi-C chromatin loop interactions, enabling the study of TF-mediated regulatory regions within a 3D genomic context. In this study, we evaluated ChIP-SP using the androgen receptor (AR) as a model TF in LNCaP prostate cancer cells. By focusing on AR ChIP-seq peaks that participate in chromatin looping and examining a 25 kb radius around each peak in 3D genomic space, ChIP-SP identified 1,499 AR-spatially regulated genes, and many of them were confirmed to be androgen-responsive. We similarly applied ChIP-SP to glucocorticoid receptor (GR) ChIP-seq data in A549 lung cancer cells and successfully identified GR-spatially regulated genes. These results demonstrate that ChIP-SP extends traditional ChIP-seq annotation into a multidimensional framework and enables the construction of a spatial cistrome for transcription factors. The tool is flexible, customizable, and holds strong potential for uncovering novel regulatory target genes, particularly in cancer biology.