# Dysregulations of functional RNA modifications and hexavalent chromium lungcarcinogenesis

> **NIH NIH R01** · STATE UNIVERSITY NEW YORK STONY BROOK · 2024 · $411,955

## Abstract

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 demonstrat...

## Key facts

- **NIH application ID:** 10741833
- **Project number:** 5R01ES032787-04
- **Recipient organization:** STATE UNIVERSITY NEW YORK STONY BROOK
- **Principal Investigator:** Chengfeng Yang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $411,955
- **Award type:** 5
- **Project period:** 2023-08-01 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10741833

## Citation

> US National Institutes of Health, RePORTER application 10741833, Dysregulations of functional RNA modifications and hexavalent chromium lungcarcinogenesis (5R01ES032787-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10741833. Licensed CC0.

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