Abstract B42: Mutant RAS represses CASZ1, a novel regulator of MYOD and MYOG, to inhibit embryonal rhabdomyosarcoma differentiation
Bibliographic record
Abstract
Abstract Embryonal rhabdomyosarcoma (ERMS) is a childhood cancer that expresses myogenic master regulatory factor MYOD but fails to differentiate. Zinc finger transcription factor CASZ1 is a tumor suppressor and orchestrates cell-fate specification, commitment, and differentiation in many cell types during development. CASZ1 is expressed during skeletal myogenesis; however, whether CASZ1 plays a role in skeletal muscle cell differentiation and RMS pathogenesis is unknown. Here we uncover that CASZ1 crosstalks with myogenic regulatory factors Myf5, MyoD, and Myog to regulate myogenesis in C2C12 cells. Public transcriptome data show that CASZ1 mRNA levels are lower in ERMS compared to normal muscle (p<0.001). CASZ1 levels decrease upon oncogenic activation of RAS-MEK pathway and increase when ERMS undergoes terminal differentiation after MEK inhibitor trametinib (MEKi) treatment. Analysis of super-enhancer landscape in MEKi-induced differentiated ERMS cells reveals a core transcriptional regulatory circuitry (CRC) including CASZ1, MYOD, and MYOG. Loss of CASZ1 attenuates MEKi-induced myogenic programming in ERMS. Restoration of CASZ1 in ERMS cells induces muscle differentiation. ChIP-seq, ATAC-seq, and RNA-seq results show that CASZ1 directly upregulates expression of skeletal muscle differentiation genes and represses non-muscle genes through affecting chromatin accessibility, enhancer maintenance, and super-enhancer activity. Next-generation sequencing of primary RMS tumors identified a nonsynonymous single-nucleotide variant causing an arginine-to-cysteine switch (R25C). When evaluated in 293T and ERMS cells, R25C impairs CASZ1 nuclear localization and fails to activate target genes’ transcription. Tumor xenograft studies show that CASZ1 suppresses RMS tumor growth (p<0.005), while the CASZ1-R25C mutant has no effect. Taken together, loss of CASZ1 activity, due to RAS-MEK signaling or genetic alteration, impairs ERMS differentiation, contributing to RMS tumorigenesis. Citation Format: Zhihui Liu, Xiyuan Zhang, Haiyan Lei, Norris Lam, Oliver Yockey, Max Xu, Arnulfo Mendoza, Jun S Wei, Javed Khan, Marielle E. Yohe, Jack F. Shern, Carol J. Thiele. Mutant RAS represses CASZ1, a novel regulator of MYOD and MYOG, to inhibit embryonal rhabdomyosarcoma differentiation [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B42.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".