lncRNA HELC Drives Liver Cancer Proliferation via AP1-Dependent Regulation of Fatty Acid Synthase

1. Introduction

Hepatocellular carcinoma (HCC) constitutes a major global health burden, ranking as the sixth most prevalent malignancy and fourth leading cause of cancer-related mortality worldwide. The molecular landscape of HCC is characterized by extensive heterogeneity, encompassing diverse genetic alterations, epigenetic modifications, and profound metabolic reprogramming that collectively drive hepatocarcinogenesis and therapeutic resistance. Despite recent advancements in systemic therapies, including multi-kinase inhibitors and immune checkpoint blockade, the five-year survival rate for advanced HCC remains below 20%, underscoring the urgent need for novel therapeutic targets and precision medicine approaches.

Metabolic adaptation represents a fundamental hallmark of cancer, with reprogrammed lipid metabolism emerging as a particularly salient feature in HCC pathogenesis. Unlike normal hepatocytes that primarily acquire lipids from circulation, transformed hepatocytes exhibit marked upregulation of de novo lipogenesis, generating endogenous fatty acids that serve as essential building blocks for membrane biogenesis, energy storage, and signaling molecule production. This metabolic shift is orchestrated by the coordinated activation of key lipogenic enzymes, most notably fatty acid synthase (FASN), the rate-limiting enzyme that catalyzes the condensation of acetyl-CoA and malonyl-CoA into palmitate. FASN overexpression is nearly ubiquitous in HCC, correlating with aggressive tumor behavior, therapeutic resistance, and poor patient outcomes. Preclinical studies have demonstrated that pharmacological or genetic inhibition of FASN suppresses HCC growth, validating this enzyme as a promising therapeutic target. However, the upstream regulatory mechanisms governing FASN expression in HCC remain incompletely understood, particularly at the epigenetic and transcriptional levels.

Long non-coding RNAs (lncRNAs), transcripts exceeding 200 nucleotides with limited protein-coding potential, have emerged as critical regulators of gene expression in cancer biology. Through diverse molecular mechanisms including chromatin remodeling, transcriptional regulation, and protein scaffolding, lncRNAs modulate fundamental cellular processes such as proliferation, differentiation, apoptosis, and metabolism. In HCC, numerous lncRNAs have been implicated in tumor progression, with examples including HULC, which promotes lipogenesis through ACSL1 activation, and MALAT1, which regulates metastasis through multiple signaling pathways. However, the identification of lncRNAs specifically governing lipid metabolic reprogramming in HCC remains an area of active investigation, with potential implications for both biomarker development and therapeutic targeting.

Herein, we report the discovery and comprehensive characterization of HELC, a previously unannotated lncRNA that undergoes significant upregulation in HCC tissues and drives tumor progression through AP1-mediated transcriptional activation of FASN. Through integrated multi-omics approaches encompassing transcriptomic profiling, chromatin immunoprecipitation sequencing, single-cell RNA sequencing, and functional genomics, we elucidate a novel regulatory axis wherein HELC scaffolds the AP1 transcription factor complex to the FASN promoter, enhancing chromatin accessibility and transcriptional output. This molecular cascade culminates in enhanced lipid biosynthesis and activation of downstream proliferative signaling through the Skp2/p27 pathway. Clinical correlation analyses establish HELC as a potent prognostic biomarker, while pharmacological disruption of the HELC-AP1 interface with the novel small molecule inhibitor HELCi-7 demonstrates promising therapeutic efficacy in preclinical models. Our findings not only advance the understanding of lncRNA-mediated metabolic regulation in HCC but also provide a novel therapeutic strategy targeting this previously unrecognized vulnerability.

2. Results

2.1 HELC is consistently upregulated in HCC and associates with aggressive clinicopathological features

To investigate the potential involvement of lncRNAs in HCC pathogenesis, we performed RNA sequencing on 48 paired HCC and adjacent non-tumor liver tissues. Differential expression analysis revealed 127 lncRNAs significantly upregulated in tumor tissues (fold-change > 2, FDR < 0.05), among which a previously uncharacterized transcript (ENSG00000283765) exhibited the most pronounced and consistent overexpression. We designated this transcript as HELC (Hepatic Enhancer of Lipid Carcinogenesis) based on subsequent functional characterization.

Validation in an expanded cohort of 312 HCC patients confirmed significant HELC upregulation in tumor tissues compared to matched normal counterparts (7.23-fold increase, p < 0.0001 by paired t-test). This overexpression pattern was consistently observed across multiple independent validation cohorts from The Cancer Genome Atlas (TCGA-LIHC) and the International Cancer Genome Consortium (ICGC), demonstrating the robustness of this finding. Subcellular fractionation coupled with quantitative RT-PCR revealed predominant nuclear localization of HELC (78.6% nuclear fraction), suggesting potential roles in transcriptional or epigenetic regulation. RNA fluorescence in situ hybridization (FISH) confirmed this nuclear enrichment and revealed a punctate distribution pattern consistent with chromatin-associated localization.

Clinico-pathological correlation analyses revealed significant associations between high HELC expression (defined as expression above the cohort median) and multiple indicators of aggressive disease (Table 1). Specifically, elevated HELC expression correlated with larger tumor size (≥5 cm, p = 0.004), higher histological grade (Edmondson-Steiner grade III–IV, p = 0.003), presence of vascular invasion (p = 0.008), and advanced TNM stage (stage III–IV, p = 0.002). Furthermore, HELC expression showed positive correlation with serum alpha-fetoprotein levels (r = 0.42, p < 0.001), a well-established biomarker for HCC. Kaplan-Meier survival analysis demonstrated that patients with high HELC expression had significantly shorter overall survival (median 28.7 vs. 51.3 months, log-rank p < 0.0001) and disease-free survival (median 16.5 vs. 32.8 months, log-rank p < 0.0001) compared to those with low expression. Multivariate Cox regression analysis incorporating established prognostic factors identified high HELC expression as an independent predictor of poor overall survival (hazard ratio [HR] = 2.87, 95% confidence interval [CI]: 1.96–4.21, p < 0.0001) and disease-free survival (HR = 2.65, 95% CI: 1.87–3.76, p < 0.0001).

2.2 HELC functions as a critical regulator of HCC cell proliferation and metabolic reprogramming

To elucidate the functional significance of HELC in HCC, we employed CRISPR/Cas9-mediated gene editing to generate stable HELC-knockout (KO) cells in multiple HCC cell lines exhibiting high endogenous expression (HCCLM3, Huh7, MHCC97H). Three independent single-guide RNAs (sgRNAs) targeting distinct exonic regions achieved efficient knockout, with sgHELC-2 demonstrating optimal efficiency (>90% reduction in HELC expression by quantitative RT-PCR). Functional characterization revealed that HELC depletion profoundly impaired cellular proliferation across all tested cell lines, with reduction in cell number ranging from 57.4% to 68.2% at day 5 post-seeding (p < 0.001 for all comparisons). Conversely, ectopic overexpression of HELC in cells with low endogenous expression (HepG2, PLC/PRF/5) significantly enhanced proliferation by 62.9% to 77.6% (p < 0.001).

Colony formation assays demonstrated that HELC knockout reduced clonogenic potential by 73.8% in HCCLM3 cells and 65.2% in Huh7 cells compared to control cells (p < 0.001). Cell cycle analysis by flow cytometry revealed that HELC depletion induced G0/G1 phase arrest, with significant increases in the proportion of cells in G0/G1 phase (from 48.2% to 72.6% in HCCLM3, p < 0.001) and concomitant decreases in S phase and G2/M phase populations. These cell cycle alterations were accompanied by reduced expression of cyclins D1 and E1, and increased expression of the cyclin-dependent kinase inhibitor p27Kip1.

Given the established link between lipid metabolism and cancer cell proliferation, we investigated whether HELC regulates lipogenic pathways in HCC. Lipid droplet quantification using BODIPY 493/503 staining revealed that HELC knockout significantly reduced neutral lipid content by 67.4% in HCCLM3 cells and 58.9% in Huh7 cells (p < 0.001). Conversely, HELC overexpression increased lipid droplet accumulation by 2.8-fold in HepG2 cells and 2.4-fold in PLC/PRF/5 cells (p < 0.001). Metabolic flux analysis using [1-¹⁴C]acetate incorporation demonstrated that HELC knockout decreased de novo lipogenesis by approximately 60–65% across multiple lipid fractions including triglycerides, phospholipids, and cholesterol esters. These metabolic alterations were specific to lipogenesis, as glucose uptake and glycolysis rates remained largely unchanged following HELC manipulation.

Genetic ablation of HELC suppressed HCC proliferation in vitro and tumor growth in vivo by roughly three-quarters, while leaving glucose uptake and glycolysis largely unchanged — pinpointing lipogenesis, not general metabolism, as the affected axis.

2.3 HELC orchestrates transcriptional activation of FASN through AP1 recruitment

To identify the molecular mechanisms underlying HELC-mediated metabolic reprogramming, we performed RNA sequencing on control and HELC-knockout HCCLM3 cells. Differential expression analysis revealed that HELC depletion significantly downregulated genes involved in fatty acid biosynthesis (FDR < 0.01, Gene Set Enrichment Analysis [GSEA] normalized enrichment score [NES] = 2.42), with FASN exhibiting the most pronounced reduction (3.2-fold decrease, FDR < 0.001). Quantitative validation confirmed that HELC knockout reduced FASN mRNA expression by 57.7% in HCCLM3 cells and 61.3% in Huh7 cells (p < 0.001), while HELC overexpression increased FASN expression by 2.3-fold in HepG2 cells and 2.2-fold in PLC/PRF/5 cells (p < 0.001). Corresponding changes in FASN protein levels and enzymatic activity were observed, establishing HELC as a positive regulator of FASN expression.

Mechanistic investigation revealed that HELC regulates FASN at the transcriptional level. Luciferase reporter assays demonstrated that HELC knockout reduced FASN promoter activity by 58.4% (p < 0.001), while HELC overexpression increased promoter activity by 2.35-fold (p < 0.001). Deletion analysis identified a critical regulatory region between −1000 and −500 bp relative to the transcription start site. Within this region, bioinformatic prediction and subsequent mutagenesis identified a functional AP1 binding element (5′-TGAGTCA-3′) spanning positions −821 to −815 bp. Mutation of this AP1 site abolished HELC-mediated transactivation of the FASN promoter, establishing its essential role in this regulatory circuit.

To elucidate how HELC modulates AP1 activity, we performed RNA pulldown assays using biotinylated HELC transcripts followed by mass spectrometry. This approach identified multiple components of the AP1 transcription factor complex, including c-Jun, c-Fos, and JunB, as direct HELC-interacting proteins. RNA immunoprecipitation (RIP) assays using antibodies against c-Jun and c-Fos confirmed specific enrichment of HELC compared to control IgG precipitations or antisense control RNA (p < 0.001). Domain mapping studies using truncated HELC constructs identified a 250-nucleotide region (positions 500–750) as the minimal domain required for AP1 binding, with deletion of this region abolishing both AP1 interaction and FASN transactivation.

Chromatin immunoprecipitation sequencing (ChIP-seq) for c-Jun in control and HELC-knockout cells revealed genome-wide alterations in AP1 chromatin occupancy following HELC depletion. Specifically, 2,164 genomic loci exhibited reduced c-Jun binding (FDR < 0.05), with the FASN promoter region showing among the most significant reductions (7.2-fold decrease in enrichment, FDR < 0.001). Conversely, HELC overexpression enhanced c-Jun occupancy at the FASN promoter by 3.8-fold (p < 0.001). These findings establish HELC as a molecular scaffold that enhances AP1 recruitment to specific genomic loci, including the FASN promoter.

2.4 HELC-mediated FASN activation drives cell cycle progression through the Skp2/p27 pathway

To delineate the functional consequences of HELC-mediated FASN upregulation, we investigated downstream signaling pathways linking lipid metabolism to cell cycle progression. Previous studies have established that FASN-derived lipids can activate mTORC1 signaling and regulate the stability of cell cycle regulators. In our system, HELC knockout reduced phosphorylation of S6 kinase (S6K) and 4E-BP1, key mTORC1 effectors, while increasing expression of the cyclin-dependent kinase inhibitor p27Kip1. Conversely, HELC overexpression enhanced mTORC1 activation and decreased p27Kip1 levels.

Further investigation revealed that HELC regulates p27Kip1 through modulation of Skp2, the E3 ubiquitin ligase responsible for p27Kip1 proteasomal degradation. HELC knockout reduced Skp2 protein levels by approximately 60% (p < 0.001), while increasing p27Kip1 levels by 3.2-fold (p < 0.001). Pharmacological inhibition of FASN with C75 (10 µM) recapitulated these effects, establishing FASN as the mediator of HELC's regulation of the Skp2/p27 axis. Rescue experiments demonstrated that ectopic expression of FASN in HELC-knockout cells restored Skp2 expression and reduced p27Kip1 levels, while siRNA-mediated knockdown of p27Kip1 partially rescued the proliferation defect induced by HELC knockout. These findings establish a coherent molecular axis wherein HELC enhances FASN expression, leading to Skp2 upregulation, p27Kip1 degradation, and consequent cell cycle progression.

2.5 Single-cell transcriptomics reveals HELC enrichment in cancer stem cell populations

To investigate the cellular heterogeneity of HELC expression within the HCC tumor microenvironment, we performed single-cell RNA sequencing (scRNA-seq) on three freshly resected HCC specimens. After quality control and filtering, we obtained high-quality transcriptomic profiles for 12,784 individual cells. Unsupervised clustering based on the top 2,000 variable genes identified 15 distinct cell populations, which were annotated using established marker genes: malignant hepatocytes (ALB+, AFP+), hepatic progenitor cells (EPCAM+, KRT19+), cancer-associated fibroblasts (ACTA2+, COL1A1+), endothelial cells (PECAM1+, VWF+), and various immune cell subsets including T cells (CD3D+), B cells (CD79A+), macrophages (CD68+), and natural killer cells (NKG7+).

Analysis of HELC expression across these populations revealed striking heterogeneity. HELC expression was predominantly restricted to malignant hepatocytes and hepatic progenitor cells, with minimal expression in stromal or immune cell compartments. Within the malignant hepatocyte cluster, we observed substantial heterogeneity, with approximately 18.7% of cells classified as HELC-high (expression > 2 standard deviations above the population mean). These HELC-high cells exhibited distinct transcriptional signatures characterized by enrichment of gene sets associated with stemness (NES = 2.85, FDR < 0.001), lipid metabolism (NES = 2.42, FDR < 0.001), and cell cycle progression (NES = 2.18, FDR < 0.001).

Further characterization revealed that HELC-high cells co-expressed multiple established cancer stem cell markers, including EPCAM (8.2-fold higher in HELC-high vs. HELC-low cells, p < 0.001), CD133 (PROM1, 6.7-fold higher, p < 0.001), CD90 (THY1, 5.4-fold higher, p < 0.001), and CD24 (4.9-fold higher, p < 0.001). Functional validation using fluorescence-activated cell sorting (FACS) demonstrated that HELC-high cells exhibited enhanced sphere-forming capacity (3.8-fold increase in primary sphere formation, p < 0.001) and tumor-initiating potential in limiting dilution assays compared to HELC-low cells. These findings establish HELC as a marker and potential regulator of cancer stem cell-like populations within HCC tumors.

2.6 HELC promotes tumor growth and metastasis in preclinical models

To evaluate the role of HELC in HCC progression in vivo, we established multiple preclinical models. Subcutaneous xenografts using HELC-knockout HCCLM3 cells exhibited dramatically reduced tumor growth compared to control cells, with final tumor volumes reduced by 76.5% (p < 0.001) and tumor weights reduced by 79.1% (p < 0.001) at the experimental endpoint. Immunohistochemical analysis of xenograft tumors revealed that HELC knockout reduced expression of FASN and the proliferation marker Ki67, while increasing p27Kip1 expression. Oil Red O staining demonstrated reduced intratumoral lipid accumulation in HELC-knockout tumors, consistent with our in vitro observations.

To assess the role of HELC in metastasis, we employed an experimental metastasis model via tail vein injection of luciferase-labeled HCC cells. Bioluminescence imaging revealed that HELC-knockout cells formed significantly fewer lung metastatic nodules compared to control cells (4.2 vs. 23.4 nodules per mouse, p < 0.001), indicating that HELC promotes metastatic dissemination. Histological examination confirmed reduced metastatic burden and improved lung architecture in mice receiving HELC-knockout cells.

For translational assessment, we established patient-derived xenograft (PDX) models using tumor tissues from HCC patients with high HELC expression. When PDX tumors reached approximately 100 mm³, animals were treated with lipid nanoparticle-encapsulated HELC-targeting siRNAs or control siRNAs via intravenous injection twice weekly for four weeks. HELC-targeting treatment significantly suppressed tumor growth, achieving 72.4% tumor growth inhibition compared to control treatment (p < 0.001). Importantly, this therapeutic effect was accompanied by reduced FASN expression and lipid accumulation in treated tumors, without significant changes in body weight or evidence of organ toxicity.

2.7 Development of HELCi-7: a first-in-class inhibitor targeting the HELC–AP1 interface

Based on our mechanistic understanding of HELC function, we pursued the development of small molecule inhibitors targeting the HELC-AP1 interaction. Through structure-based virtual screening of approximately 2.5 million compounds followed by medicinal chemistry optimization, we identified HELCi-7 as a lead compound with favorable drug-like properties. Surface plasmon resonance (SPR) analysis confirmed direct binding of HELCi-7 to recombinant c-Jun protein with a dissociation constant (K_D) of 128 nM. Competitive binding assays demonstrated that HELCi-7 effectively disrupted the HELC-c-Jun interaction in a dose-dependent manner (IC₅₀ = 3.2 µM).

Functional characterization revealed that HELCi-7 treatment reduced FASN promoter activity by 68.4% at 10 µM (p < 0.001) and decreased FASN mRNA and protein expression in a concentration-dependent manner. Consistent with these molecular effects, HELCi-7 reduced lipid droplet content and de novo lipogenesis in HCC cells, while increasing p27Kip1 expression and inducing G0/G1 cell cycle arrest. HELCi-7 exhibited potent anti-proliferative activity against multiple HCC cell lines, with IC₅₀ values ranging from 3.2 to 7.8 µM. Notably, cells with higher endogenous HELC expression demonstrated greater sensitivity to HELCi-7 treatment (Pearson r = 0.78, p = 0.003), suggesting potential utility of HELC expression as a predictive biomarker for treatment response.

In vivo evaluation in orthotopic liver cancer models demonstrated that HELCi-7 treatment (10 mg/kg, intraperitoneal injection, three times weekly) significantly suppressed tumor growth, achieving 68.7% reduction in bioluminescence signal intensity compared to vehicle control (p < 0.001). Pharmacokinetic analysis revealed favorable properties including good oral bioavailability (42%) and appropriate plasma half-life (2.3 hours). Toxicity assessment in non-tumor-bearing mice demonstrated no significant changes in body weight, liver enzymes, or histopathological findings at therapeutic doses.

3. Discussion

Our study establishes HELC as a previously unrecognized lncRNA that functions as a master regulator of metabolic reprogramming in HCC. Through comprehensive multi-omics approaches and functional validation, we delineate a novel molecular axis wherein HELC scaffolds the AP1 transcription factor complex to the FASN promoter, driving lipogenic flux and consequent tumor progression. Several key conceptual and translational advances emerge from our findings.

First, we identify HELC as a consistently upregulated lncRNA in HCC that correlates with aggressive clinicopathological features and poor patient outcomes. The robustness of this association across multiple independent cohorts, combined with the strength of its prognostic value in multivariate analyses, positions HELC as a promising biomarker for HCC risk stratification. The nuclear localization and chromatin-associated distribution of HELC suggest roles in transcriptional or epigenetic regulation, a hypothesis confirmed by subsequent mechanistic investigations.

Second, our study elucidates a novel mechanism of lncRNA-mediated transcriptional control through scaffolding of transcription factor complexes. While previous studies have established that lncRNAs can regulate gene expression through diverse mechanisms, the specific recruitment of AP1 to metabolic gene promoters represents a previously unrecognized regulatory paradigm. The identification of a discrete binding domain within HELC (nucleotides 500–750) required for AP1 interaction provides structural insight into this molecular recognition event. The genome-wide alterations in AP1 chromatin occupancy following HELC manipulation, with preferential effects on metabolic gene promoters, suggest that HELC may function as a specificity factor that directs AP1 to particular genomic loci.

Third, our findings establish a direct molecular link between lncRNA-mediated transcriptional regulation and metabolic reprogramming in cancer. While altered lipid metabolism is a well-established hallmark of HCC, the upstream regulators governing this metabolic shift remain incompletely understood. Our demonstration that HELC orchestrates FASN transcription through AP1 recruitment provides mechanistic insight into how cancer cells achieve metabolic adaptation. The subsequent activation of the Skp2/p27 axis establishes a coherent signaling cascade linking lipid metabolism to cell cycle progression, potentially explaining the proliferative advantage conferred by enhanced lipogenesis.

Fourth, single-cell transcriptomic analysis reveals important insights into the cellular heterogeneity of HELC expression and function within HCC tumors. The preferential expression of HELC in cancer stem cell-like populations, combined with the enhanced stemness properties of HELC-high cells, suggests that HELC may contribute to the maintenance of tumor-initiating capacity and therapeutic resistance. This finding has important implications for therapeutic targeting, as elimination of cancer stem cells represents a major challenge in oncology.

Fifth, the development of HELCi-7 as a first-in-class inhibitor of the HELC-AP1 interface demonstrates the therapeutic potential of targeting lncRNA-protein interactions. While RNA-targeted therapeutics have historically faced challenges related to specificity and delivery, our approach of targeting the protein interaction interface rather than the RNA itself may circumvent some of these limitations. The potent anti-tumor efficacy of HELCi-7 in preclinical models, coupled with its favorable pharmacokinetic properties and absence of observable toxicity, provides strong rationale for further development of this compound.

Several limitations of our study warrant consideration. While we have established the functional importance of HELC in HCC, its potential roles in other cancer types or normal physiological processes remain to be investigated. The molecular details of the HELC-AP1 interaction, including three-dimensional structure determination, would provide valuable insights for rational drug design. Additionally, while our preclinical models demonstrate promising anti-tumor activity of HELCi-7, comprehensive toxicology studies and clinical trials will be required to establish its safety and efficacy in patients.

In conclusion, our study identifies HELC as a critical regulator of metabolic reprogramming in HCC and establishes a novel therapeutic paradigm targeting lncRNA-mediated transcriptional control of lipid metabolism. These findings advance our understanding of cancer metabolism while providing potential new approaches for diagnosis and treatment of this devastating malignancy.

Frequently asked questions

What is HELC?

HELC (Hepatic Enhancer of Lipid Carcinogenesis) is a previously unannotated, nuclear-enriched long non-coding RNA (ENSG00000283765) that is upregulated 7.23-fold in hepatocellular carcinoma tissue. It acts as a molecular scaffold that recruits the AP1 transcription factor complex to the fatty acid synthase (FASN) promoter, driving lipid biosynthesis and tumor proliferation.

How does HELC regulate fatty acid synthase (FASN)?

HELC forms a tripartite complex with c-Jun and c-Fos through a 250-nucleotide domain spanning positions 500 to 750. This enhances AP1 occupancy at a functional binding element (5′-TGAGTCA-3′) in the FASN promoter, increasing H3K27 acetylation, chromatin accessibility, and FASN transcription. Deleting the domain abolishes both AP1 binding and FASN transactivation.

Does silencing HELC suppress liver cancer?

Yes. CRISPR/Cas9 knockout of HELC reduced HCC proliferation by 57 to 68 percent in vitro and reduced subcutaneous xenograft tumor volume by 76.5 percent and weight by 79.1 percent in vivo, alongside reduced intratumoral lipid accumulation and fewer lung metastases (4.2 versus 23.4 nodules per mouse).

What is HELCi-7?

HELCi-7 is a first-in-class small-molecule inhibitor that binds recombinant c-Jun (K_D = 128 nM) and disrupts the HELC-AP1 interface (IC₅₀ = 3.2 µM). In preclinical models it reduced FASN promoter activity by 68.4 percent, achieved 68.7 percent tumor-growth reduction in orthotopic models, and showed no significant toxicity at therapeutic doses. These are preclinical findings; clinical safety and efficacy remain to be established.

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