The mitochondrial RNA polymerase POLRMT promotes skin squamous cell carcinoma cell growth

Abstract

RNA polymerase mitochondrial (POLRMT) expression and the potential biological functions in skin squamous cell carcinoma (SCC) were explored. We showed that POLRMT is significantly elevated in skin SCC. Genetic depletion of POLRMT, using shRNA-induced knockdown or CRISPR/Cas9-mediated knockout (KO), resulted in profound anti-skin SCC cell activity. In patient-derived primary skin SCC cells or immortalized lines (A431 and SCC-9), POLRMT shRNA or KO potently suppressed mitochondrial DNA (mtDNA) transcription and suppressed cell viability, proliferation and migration. POLRMT shRNA or KO impaired mitochondrial functions in different skin SCC cells, leading to production of ROS (reactive oxygen species), depolarization of mitochondria and depletion of ATP. Moreover, mitochondrial apoptosis cascade was induced in POLRMT-depleted skin SCC cells. IMT1, a POLRMT inhibitor, largely inhibited proliferation and migration, while inducing depolarization of mitochondria and apoptosis in primary skin SCC cells. Contrarily, ectopic overexpression of POLRMT increased mtDNA transcription and augmented skin SCC cell growth. Importantly, POLRMT shRNA adeno-associated virus injection robustly hindered growth of the subcutaneous A431 xenografts in mice. In the POLRMT shRNA virus-treated A431 xenograft tissues, POLRMT depletion, mtDNA transcription inhibition, cell apoptosis, lipid peroxidation and ATP depletion were detected. Together, overexpressed POLRMT increases mtDNA transcription and promotes skin SCC growth.

POLRMT over‐expression is linked to WNT/beta‐catenin signaling, immune infiltration, and unfavorable outcomes in lung adenocarcinoma patients

“…Besides the role of POLRMT in NSCLC, recently published studies have revealed the protumoral role of POLRMT in skin squamous cell carcinoma, osteosarcoma, acute myeloid leukemia, and breast cancer. Considering the role of POLRMT in mtDNA transcription, these studies assessed the transcripts of mtDNA genes (e.g., mitochondrial mRNA levels, subunits of respiratory chain complexes, and S6 phosphorylation), and found that the expression of these genes decreased with decreasing POLRMT expression 5,6,7,10 . However, these studies did not assess whether POLRMT was involved in any biological pathway linked to cancer development.…”

“…Considering the role of POLRMT in mtDNA transcription, these studies assessed the transcripts of mtDNA genes (e.g., mitochondrial mRNA levels, subunits of respiratory chain complexes, and S6 phosphorylation), and found that the expression of these genes decreased with decreasing POLRMT expression. 5,6,7,10 However, these studies did not assess whether POLRMT was involved in any biological pathway linked to cancer development. Through GSEA, we found that high-level expression of POLRMT was linked to MYC targets and Wnt/beta-catenin signaling, both of which had a role in lung cancer cell processes and proliferation.…”

“…Mutations in the gene encoding POLRMT directly impact transcription levels, thereby causing dysfunction in key mitochondrial processes such as oxidative phosphorylation, eventually leading to the development of malignant tumors. A growing body of evidence indicates that POLRMT expression is associated with various cancers, including skin squamous cell carcinoma, 5 osteosarcoma, 6 acute myeloid leukemia, 7,8 and breast cancer. 9 Our recent study also revealed that POLRMT expression promoted non-small cell lung cancer (NSCLC) proliferation in cell lines and xenografts 10 ; however, the study did not use tissues from cancer patients to examine the role of POLRMT in tumor formation and shed less light on underlying mechanism.…”

Mitochondria transcription and cancer

“…Mitochondrial transcription dysregulation has been implicated in various diseases [ 35 – 39 ], including cancer [ 9 , 40 – 45 ]. In cancer cells, alterations in mitochondrial transcription can contribute to tumor development and progression [ 9 , 40 , 41 ]. Dysregulated mitochondrial transcription can result in aberrant expression of mitochondrial genes involved in energy production, apoptosis, and other cellular processes [ 33 , 46 – 48 ].…”

“…POLRMT is a core component of the mitochondrial transcription machinery and is closely associated with tumor progression. Studies have shown that increased expression of POLRMT is observed in lung cancer [ 9 ], osteosarcoma [ 10 ], squamous cell carcinoma [ 41 ], endometrial cancer [ 40 ], and acute myeloid leukemia [ 77 , 78 ], and it can promote tumor cell proliferation, invasion, and migration abilities. The high expression of POLRMT is directly associated with poor prognosis in cancer patients [ 9 , 41 , 79 ].…”