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Principal Investigator: Yang, Chengfeng
Institute Receiving Award State University New York Stony Brook
Location Stony Brook, NY
Grant Number R01ES032787
Funding Organization National Institute of Environmental Health Sciences
Award Funding Period 01 Aug 2023 to 30 Nov 2026
DESCRIPTION (provided by applicant): PROJECT SUMMARY/ABSTRACT Hexavalent chromium [Cr(VI)] is one of the most common environmental carcinogens causing lung cancer, however, the mechanism of Cr(VI) carcinogenesis remains elusive. The N6-methyladenosine (m6A) modification is the most prevalent internal modification in eukaryotic messenger RNAs (mRNAs), which is dynamically regulated by three groups of proteins known as writers, erasers and readers. Recent advances in demonstrating the vital roles of RNA m6A modifications in regulating gene expression and a variety of biological processes represents a breakthrough in understanding RNA biology and functions. Moreover, accumulating evidence has shown that up- regulation of m6A modifications plays critical roles in cancer progression and cancer therapy resistances. However, it remains largely un-explored whether the m6A modification dysregulation plays a role in the carcinogenic process especially in environmental carcinogenesis. The goal of this study is to investigate the mechanism of Cr(VI) carcinogenesis by studying RNA m6A modification dysregulations, focusing on the role and mechanism of chronic Cr(VI) exposure-caused m6A writer methyltransferase like 3 (METTL3) up-regulation. Our preliminary studies found: (i) Chronic Cr(VI) exposure up-regulates METTL3 expression, which contributes causally to Cr(VI)-induced cell transformation, CSC-like property and tumorigenesis. (ii) METTL3 up-regulation is also similarly detected in chronic Cr(VI) exposure-caused human and mouse lung tumor tissues. (iii) The Jak2-Stat3 pathway is activated. (iv) Jak2 and SOCS3 mRNA levels are increased and decreased in Cr(VI)-transformed cells, respectively. Stably knocking down METTL3 significantly decreases Jak2 but increases SOCS3 mRNA levels. (v) Inhibition of the Jak2-Stat3 oncogenic pathway in Cr(VI)-transformed cells significantly reduces their CSC-like property. (vi) The repressive histone 2A (H2A) lysine 119 (K119) monoubiquitination (H2AK119ub1) levels and H2AK119ub1 enrichment at METTL3 promoter region are greatly reduced in Cr(VI)-transformed cells. (vii) The expression level of a H2A deubiquitinase USP28 is up-regulated in Cr(VI)-transformed cells. Knockdown of USP28 increases H2AK119ub1 levels but reduces METTL3 protein levels. Based on literature review and our novel preliminary data, our central hypothesis is: “METTL3 up-regulation increases Jak2 and SOCS3 mRNA m6A modifications to up-regulate Jak2 but down-regulate SOCS3 expressions, which activates the oncogenic Jak2-Stat3 pathway promoting Cr(VI) carcinogenesis”. Three aims are proposed: Aim 1 will determine the mechanism of how chronic Cr(VI) exposure up- regulates METTL3 expression focusing on the role of USP28-mediated down-regulation of histone 2A monoubiquitination. Aim 2 will demonstrate that METTL3 up-regulation increases Jak2 and SCOS3 mRNA m6A modifications to activate the Jak2-Stat3 pathway promoting Cr(VI)-exposure-induced CSC-like property and tumorigenesis. Aim 3 will demonstrate that METTL3 lung-specific deletion using a METTL3 conditional knockout mouse model impairs Cr(VI) lung tumorigenesis in mice.
Science Code(s)/Area of Science(s) Primary: 10 - Epigenetics
Secondary: 03 - Carcinogenesis/Cell Transformation
Publications See publications associated with this Grant.
Program Officer Frederick Tyson
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