Targeting HSPA1A in ARID2-deficient lung adenocarcinoma
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Published on: January 19, 2019
Xue Wang1, Yuetong Wang1, Zhaoyuan Fang1
1State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China.
Abstract:
Somatic mutations of the chromatin remodeling gene ARID2 are observed in ∼7% of human lung adenocarcinomas (LUADs). However, the role of ARID2 in the pathogenesis of LUADs remains largely unknown. Here we find that ARID2 expression is decreased during the malignant progression of both human and mice LUADs. Using two Kras -based genetically engineered murine models, we demonstrate that ARID2 knockout significantly promotes lung cancer malignant progression and shortens overall survival. Consistently, ARID2 knockdown significantly promotes cell proliferation in human and mice lung cancer cells. Through integrative analyses of ChIP-Seq and RNA-Seq data, we find that Hspa1a is up-regulated by Arid2 loss. Knockdown of Hspa1a specifically inhibits malignant progression of Arid2-deficient but not Arid2-wt lung cancers in both cell lines as well as animal models. Treatment with an HSPA1A inhibitor could significantly inhibit the malignant progression of lung cancer with ARID2 deficiency. Together, our findings establish ARID2 as an important tumor suppressor in LUADs with novel mechanistic insights, and further identify HSPA1A as a potential therapeutic target in ARID2-deficient LUADs.
Insights
Loss of the ARID2 gene promotes lung cancer progression and reduces survival in lung adenocarcinoma (LUAD). Targeting HSPA1A offers a potential therapeutic strategy for ARID2-deficient LUAD.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Somatic mutations in ARID2 occur in approximately 7% of human lung adenocarcinomas (LUADs).
- The specific role of ARID2 in LUAD pathogenesis is not well understood.
Purpose of the Study:
- To investigate the function of ARID2 in lung adenocarcinoma.
- To elucidate the molecular mechanisms underlying ARID2's role in LUAD.
- To identify potential therapeutic targets for ARID2-deficient LUAD.
Main Methods:
- Utilized Kras-based genetically engineered murine models for LUAD.
- Performed ARID2 knockout and knockdown experiments in human and murine lung cancer cells.
- Conducted integrative analyses of ChIP-Seq and RNA-Seq data.
- Evaluated the efficacy of HSPA1A inhibition in preclinical models.
Main Results:
- ARID2 expression decreases during LUAD malignant progression in humans and mice.
- ARID2 deficiency promotes lung cancer progression and reduces survival in murine models.
- ARID2 knockdown enhances lung cancer cell proliferation.
- ARID2 loss up-regulates HSPA1A expression.
- HSPA1A knockdown or inhibition suppresses malignant progression in ARID2-deficient LUAD.
Conclusions:
- ARID2 acts as a tumor suppressor in lung adenocarcinoma.
- ARID2 deficiency promotes LUAD progression partly through HSPA1A up-regulation.
- HSPA1A is a potential therapeutic target for ARID2-deficient LUAD.
