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The transcription elongation factor TCEA3 induces apoptosis in rhabdomyosarcoma.

ABSTRACT: TCEA3 is one of three genes representing the transcription elongation factor TFIIS family in vertebrates. TCEA3 is upregulated during skeletal muscle differentiation and acts to promote muscle specific gene expression during myogenesis. Rhabdomyosarcoma (RMS) is a pediatric cancer derived from the muscle lineage, but the expression or function of TCEA3 in RMS was uncharacterized. We found that TCEA3 expression was strongly inhibited in RMS cell lines representing both ERMS and ARMS subtypes of RMS. TCEA3 expression correlates with DNA methylation and we show that TBX2 is also involved in the repression of TCEA3 in RMS cell lines. Ectopic expression of TCEA3 inhibited proliferation of RMS cell lines and initiated apoptosis through both the intrinsic and extrinsic pathways. We found that only pan-caspase inhibitors could block apoptosis in the presence of TCEA3. While expression of TCEA3 is highest in skeletal muscle, expression has been detected in other tissues as well, including breast, ovarian and prostate. We found that ectopic expression of TCEA3 also promotes apoptosis in HeLa, MCF7, MDA-231, and PC3 cell lines, representing cervical, breast, and prostate cancer, respectively. Restoration of TCEA3 expression in RMS cell lines enhanced sensitivity to chemotherapeutic drugs, including TRAIL. Thus, TCEA3 presents a novel target for therapeutic strategies to promote apoptosis and enhance sensitivity to current chemotherapeutic drugs.

SUBMITTER: Kazim N

PROVIDER: S-EPMC6985194 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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The transcription elongation factor TCEA3 induces apoptosis in rhabdomyosarcoma.

Kazim Noor N Adhikari Abhinav A Oh Teak Jung TJ Davie Judith J

Cell death & disease 20200127 1

TCEA3 is one of three genes representing the transcription elongation factor TFIIS family in vertebrates. TCEA3 is upregulated during skeletal muscle differentiation and acts to promote muscle specific gene expression during myogenesis. Rhabdomyosarcoma (RMS) is a pediatric cancer derived from the muscle lineage, but the expression or function of TCEA3 in RMS was uncharacterized. We found that TCEA3 expression was strongly inhibited in RMS cell lines representing both ERMS and ARMS subtypes of R ...[more]

PMID: 31988307

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Project description:Under conditions of tight coupling between translation and transcription, the ribosome enables synthesis of full-length mRNAs by preventing both formation of intrinsic terminator hairpins and loading of the transcription termination factor Rho. While previous studies have focused on transcription factors, we investigated the role of Escherichia coli elongation factor P (EF-P), an elongation factor required for efficient translation of mRNAs containing consecutive proline codons, in maintaining coupled translation and transcription. In the absence of EF-P, the presence of Rho utilization (rut) sites led to an ~30-fold decrease in translation of polyproline-encoding mRNAs. Coexpression of the Rho inhibitor Psu fully restored translation. EF-P was also shown to inhibit premature termination during synthesis and translation of mRNAs encoding intrinsic terminators. The effects of EF-P loss on expression of polyproline mRNAs were augmented by a substitution in RNA polymerase that accelerates transcription. Analyses of previously reported ribosome profiling and global proteomic data identified several candidate gene clusters where EF-P could act to prevent premature transcription termination. In vivo probing allowed detection of some predicted premature termination products in the absence of EF-P. Our findings support a model in which EF-P maintains coupling of translation and transcription by decreasing ribosome stalling at polyproline motifs. Other regulators that facilitate ribosome translocation through roadblocks to prevent premature transcription termination upon uncoupling remain to be identified. Bacterial mRNA and protein syntheses are often tightly coupled, with ribosomes binding newly synthesized Shine-Dalgarno sequences and then translating nascent mRNAs as they emerge from RNA polymerase. While previous studies have mainly focused on the roles of transcription factors, here we investigated whether translation factors can also play a role in maintaining coupling and preventing premature transcription termination. Using the polyproline synthesis enhancer elongation factor P, we found that rapid translation through potential stalling motifs is required to provide efficient coupling between ribosomes and RNA polymerase. These findings show that translation enhancers can play an important role in gene expression by preventing premature termination of transcription.

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The transcription elongation factor TCEA3 induces apoptosis in rhabdomyosarcoma.

Publications

The transcription elongation factor TCEA3 induces apoptosis in rhabdomyosarcoma.

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