Integrative analysis of non-small cell lung cancer identifies Jumonji domain-containing 6/ETS homologous factor axis as a target to overcome radioresistance – Nature

Executive Summary

This report details an integrative study on non-small cell lung cancer (NSCLC), focusing on mechanisms of radioresistance and metastasis following radiation therapy (RT). The research aligns with the United Nations Sustainable Development Goal 3 (SDG 3), which aims to ensure good health and well-being, particularly Target 3.4, focused on reducing premature mortality from non-communicable diseases like cancer. The study identifies the Jumonji domain-containing 6 (JMJD6)/ETS homologous factor (EHF) axis as a critical driver of treatment failure. Key findings indicate that JMJD6 is a potential therapeutic target to enhance the efficacy of radiotherapy, thereby contributing to improved health outcomes and supporting global sustainable development objectives.

• Primary Finding: Radiation therapy upregulates JMJD6 in NSCLC, which promotes tumor metastasis and radioresistance.
• Mechanism Identified: JMJD6 activates the transcription of EHF through the epigenetic demethylation of H4R3me2s at the EHF promoter.
• Therapeutic Implication: Targeting the JMJD6/EHF axis inhibits cancer cell proliferation, metastasis, and cancer stem-like cell (CSC) properties post-radiotherapy.
• SDG Relevance: The identification of this novel therapeutic target directly supports SDG 3 by advancing cancer treatment to reduce mortality from a leading non-communicable disease.

Introduction: Aligning Cancer Research with Global Health Goals

The Global Burden of Lung Cancer and SDG 3

Lung cancer remains the leading cause of cancer-related mortality worldwide, posing a significant obstacle to achieving SDG Target 3.4, which calls for a one-third reduction in premature mortality from non-communicable diseases by 2030. Radiation therapy (RT) is a cornerstone of lung cancer treatment, utilized in a majority of cases to achieve local tumor control. However, its long-term success is frequently undermined by radioresistance, leading to tumor recurrence and metastasis, which directly impedes progress toward global health targets.

Challenges in Radiotherapy and the Role of Innovation (SDG 9)

The development of radioresistance is a complex process involving cellular subpopulations known as cancer stem-like cells (CSCs), which possess enhanced DNA repair capabilities and are resistant to conventional therapies. Radiation can paradoxically enrich this CSC population, creating a cycle of treatment failure. Addressing this challenge requires scientific innovation and advanced research, aligning with SDG 9’s emphasis on upgrading technological capabilities and enhancing scientific research. This study explores the epigenetic mechanisms that underpin radioresistance, seeking to develop novel therapeutic strategies that integrate targeted therapies with RT.

Study Objectives in the Context of Sustainable Development

This research aims to dissect the molecular mechanisms driving post-radiotherapy metastasis in NSCLC. The central hypothesis is that the epigenetic regulator JMJD6 drives radioresistance by reprogramming cancer cells toward a stem-like state. By identifying the key downstream targets of JMJD6, such as EHF, this study provides a rationale for a novel combinatorial therapeutic strategy. The ultimate objective is to improve the durability of radiotherapy, offering a tangible contribution to SDG 3 by enhancing treatment outcomes and reducing cancer mortality.

Methodology and Research Framework

Integrative Analytical Approach

To investigate gene alterations induced by radiotherapy, a multi-faceted approach was employed, reflecting a commitment to robust scientific inquiry and knowledge sharing (SDG 17). The methods included:

• Analysis of human NSCLC tissue arrays.
• Bulk RNA-sequencing and single-cell RNA-sequencing of publicly available datasets (e.g., TCGA).
• CUT&Tag sequencing to identify protein-DNA interactions.

In Vitro and In Vivo Models

The functional role of the JMJD6/EHF axis was validated through a series of experiments designed to model the clinical scenario of post-RT metastasis. These included:

1. In Vitro Experiments: Human NSCLC cell lines (A549, H1299) were used to assess cell migration, proliferation, and stemness properties following gene knockdown and radiation exposure.
2. Animal Studies: An experimental lung metastatic mouse model was established to evaluate the in vivo effects of JMJD6 and EHF knockdown on tumor metastasis following RT.

Key Findings and Implications for SDG 3

JMJD6 as a Prognostic Marker in Non-Small Cell Lung Cancer (NSCLC)

The investigation revealed a clear correlation between JMJD6 expression and patient outcomes, providing a valuable biomarker for identifying high-risk individuals and tailoring treatments to meet the goals of SDG 3.

• JMJD6 expression is significantly upregulated in NSCLC tumor tissues compared to adjacent normal tissues.
• Elevated JMJD6 levels are strongly associated with poor overall survival and a higher incidence of tumor metastasis in NSCLC patients.
• Single-cell RNA-sequencing data confirmed increased JMJD6 expression specifically within the epithelial cells of tumor samples.

Impact of Radiotherapy on the JMJD6/EHF Axis

The study identified a critical molecular pathway induced by radiotherapy that contributes to treatment resistance, a primary barrier to achieving SDG 3.4.

• Ionizing radiation (IR) upregulates JMJD6 expression in NSCLC cells, particularly within the CSC (CD44+/CD133+) subpopulation.
• JMJD6 directly binds to the promoter of the EHF gene and activates its transcription by demethylating the repressive histone mark H4R3me2s.
• This IR-JMJD6-EHF signaling axis represents a key mechanism of acquired radioresistance.

Targeting the JMJD6/EHF Axis to Overcome Radioresistance

Experimental validation demonstrated that inhibiting the JMJD6/EHF axis can sensitize NSCLC cells to radiotherapy, presenting a promising therapeutic strategy.

• Genetic knockdown of JMJD6 suppressed post-RT cell migration, proliferation, and sphere-forming capacity (a measure of stemness) in vitro.
• In vivo, JMJD6 knockdown significantly reduced the formation of lung metastases in mouse models, both with and without prior radiation treatment.
• Knockdown of the downstream effector, EHF, recapitulated these anti-metastatic and anti-stemness effects, confirming its role in mediating JMJD6’s function.
• The effects of EHF appear to be mediated through the inhibition of the TGF-β/SMAD and AKT/ERK signaling pathways, which are known drivers of metastasis.

Discussion: Advancing Cancer Treatment for Sustainable Health Outcomes

JMJD6 as a Therapeutic Target for NCDs

This report establishes JMJD6 as a driver of radioresistance and metastasis in NSCLC. The findings suggest that elevated JMJD6 levels following radiotherapy create a permissive environment for the expansion of aggressive, treatment-refractory CSCs. Therefore, JMJD6 represents a promising therapeutic target. The development of JMJD6 inhibitors, used in combination with radiotherapy, could significantly improve treatment efficacy, directly contributing to the SDG 3.4 goal of reducing premature mortality from non-communicable diseases.

The Role of Cancer Stem Cells in Treatment Failure

The study underscores the critical role of CSCs in tumor relapse. By demonstrating that JMJD6 is a key epigenetic mediator of the transition to a stem-like state post-radiation, this research provides crucial insight into developing more durable cancer therapies. Eradicating or preventing the induction of CSCs is essential for achieving long-term tumor control and improving patient survival, aligning with the overarching aims of SDG 3.

Future Directions and Clinical Relevance

The identification of the IR-JMJD6-EHF axis provides a strong rationale for clinical investigation. Future studies should focus on assessing the safety and efficacy of combining pharmacological JMJD6 inhibitors with standard radiotherapy regimens for NSCLC. This line of research supports SDG Target 3.b, which encourages the research and development of medicines for non-communicable diseases that disproportionately affect global populations.

Conclusion: Contribution to Sustainable Development Goal 3

In summary, this report identifies the JMJD6/EHF axis as a critical regulator of radioresistance and metastasis in NSCLC. JMJD6 is upregulated by radiation and epigenetically activates EHF, which in turn promotes CSC properties and metastatic potential through key signaling pathways. Targeting this axis effectively inhibits these processes in preclinical models. These findings provide a novel therapeutic strategy to overcome a significant clinical challenge in oncology. By advancing the understanding and treatment of lung cancer, this research directly supports the global effort to achieve Sustainable Development Goal 3, promoting good health and well-being for all.

Analysis of Sustainable Development Goals in the Article

1. Which SDGs are addressed or connected to the issues highlighted in the article?

The primary Sustainable Development Goal (SDG) addressed in the article is:

• SDG 3: Good Health and Well-being

Explanation:

The article’s entire focus is on improving human health by tackling a major global health challenge. It directly addresses the goal of ensuring healthy lives and promoting well-being by conducting in-depth research into lung cancer, which the article identifies as “the predominant cause of cancer-related mortality globally.” The study aims to understand and overcome radioresistance in non-small cell lung cancer (NSCLC) to “improve the durability of the benefits of radiotherapy for lung cancer patients” and ultimately reduce mortality from this non-communicable disease (NCD).

2. What specific targets under those SDGs can be identified based on the article’s content?

Based on the article’s focus on cancer research and treatment, the following specific targets under SDG 3 can be identified:

1. Target 3.4: By 2030, reduce by one-third premature mortality from non-communicable diseases through prevention and treatment and promote mental health and well-being.

   Explanation:

   Lung cancer is a leading non-communicable disease. The research presented in the article is directly aimed at improving treatment outcomes and reducing mortality. The study investigates why a key treatment, radiation therapy, fails, and seeks to find solutions. This is supported by statements such as:

   • The introduction notes that advances in targeted therapies have “contributed to a reduction in the mortality rate of NSCLC patients.”
   • The study identifies that elevated levels of the JMJD6 gene are linked to “unfavorable outcomes” and “worse prognosis,” which are directly related to mortality.
   • The ultimate goal is to develop “a novel combinatorial therapeutic strategy to overcome treatment failure,” which would directly contribute to reducing premature deaths from lung cancer.

2. Target 3.b: Support the research and development of vaccines and medicines for the communicable and non-communicable diseases…

   Explanation:

   The article is a clear example of fundamental medical research and development (R&D) for a major NCD. It does not just describe the problem but actively seeks to find a solution by identifying a new therapeutic pathway. This is evident through:

   • The study’s objective “to investigate new mechanisms of metastasis after RT for NSCLC” and “dissect the molecular mechanisms underpinning the radioresistance of lung cancer.”
   • The conclusion that “JMJD6 as a promising therapeutic target to attenuate post-RT metastasis” and the call for “future clinical studies… to assess the safety and efficacy of combining pharmacological JMJD6 inhibitors with radiotherapy.” This highlights the study’s role in the R&D pipeline for new cancer medicines.

3. Are there any indicators mentioned or implied in the article that can be used to measure progress towards the identified targets?

Yes, the article mentions and implies several indicators that can be used to measure progress towards the identified targets.

1. Indicators for Target 3.4 (Reduce premature mortality from NCDs)

   The official indicator is 3.4.1: Mortality rate attributed to… cancer… The article provides direct and proxy measures for this indicator:

   • Mortality Rate: The article explicitly mentions “cancer-related mortality” and the “mortality rate of NSCLC patients,” establishing this as a key metric for the problem it addresses.
   • Overall Survival (OS): The study uses Overall Survival time as a primary indicator of patient outcomes. For example, it states, “the overall survival (OS) time of LUSC patients with low and high JMJD6 expression was 51.0 ± 25.4 and 28.0 ± 23.0 months respectively.” This is a direct quantitative measure used to assess factors influencing mortality.
   • Survival Rates: The analysis of TCGA data showed that “LUAD patients with higher expression of JMJD6 demonstrated decreased survival rates.” This is another direct measure of mortality risk.
   • Prognosis: The article repeatedly links high JMJD6 expression to a “worse prognosis” and “unfavorable outcomes,” which are qualitative but critical indicators of mortality risk.

2. Indicators for Target 3.b (Support R&D of new medicines)

   While the article doesn’t provide a quantitative indicator like R&D spending, the research activities and outcomes themselves serve as qualitative indicators of progress in medical R&D:

   • Identification of Therapeutic Targets: The identification of “JMJD6 as a potential therapeutic target” is a key milestone in the R&D process for new drugs.
   • Elucidation of Molecular Mechanisms: The detailed investigation of the “JMJD6/EHF axis” and its role in radioresistance is a fundamental R&D activity that provides the “rationale for a novel combinatorial therapeutic strategy.”
   • Preclinical Research Activities: The use of advanced research methods such as “bulk RNA-sequencing, CUT&Tag sequencing, single-cell RNA-sequencing… in vitro experiments and animal studies” are tangible indicators of ongoing R&D efforts to develop new treatments.

4. Summary Table of SDGs, Targets, and Indicators

Source: nature.com