Decreased PPM1B Expression Drives PRMT5-Mediated Histone Modification in Lung Cancer Progression

TL;DR

This study shows that reduced PPM1B levels in lung cancer lead to aggressive tumor growth through a pathway involving PRMT5 and histone modification.

Contribution

The study identifies a novel PPM1B-MP-PRMT5 pathway in lung cancer progression and establishes PPM1B as a potential prognostic marker.

Findings

PPM1B expression is significantly reduced in lung SCC and ADC compared to normal tissues.

Loss of PPM1B correlates with increased PRMT5 activity and poor patient survival in SCC.

Reduced PPM1B leads to histone H2A dimethylation and suppression of tumor suppressor genes.

Abstract

Pulmonary carcinoma remains a highly aggressive malignancy driven by complex signaling and epigenetic dysregulation. This study investigates a novel oncogenic pathway involving the Mg2+/Mn2+-dependent protein phosphatase 1B PPM1B/myosin phosphatase (MP)/protein arginine methyltransferase 5 (PRMT5) axis, which promotes carcinogenesis by symmetrically dimethylating histone H2A and suppressing tumor suppressor genes. We hypothesized that loss of PPM1B would activate this pathway and drive tumorigenesis. Western blotting, PCR, and immunohistochemistry revealed a significant reduction in PPM1B expression in both squamous cell carcinoma (SCC) and human lung adenocarcinoma (ADC) compared to normal lung tissues, which correlated with worse patient survival. Despite an increase in total MYPT1, the regulatory subunit of MP, its inhibitory phosphorylation at Thr853 was significantly elevated in both tumor types. The inactivation of MP corresponded with a significant increase in the activating phosphorylation of PRMT5 at Thr80, especially in SCC, which was linked to a particularly poor prognosis. Downstream, this resulted in a dramatic elevation in the symmetric dimethylation of histone H2A, leading to decreased expression of retinoblastoma protein. Our findings demonstrate that decreased PPM1B expression drives the oncogenic activation of the MP/PRMT5 axis. This mechanism contributes to the aggressive nature of SCC, establishing PPM1B as a promising prognostic marker in lung cancer.

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