Mechanisms of cancer stem cells drug resistance and the pivotal role of HMGA2

Huldani, Huldani; Jasim, Saade Abdalkareem; Sergeenva, Klunko Nataliya; Bokov, Dmitry Olegovich; Abdelbasset, Walid Kamal; Туракулов, Р. И.; Al‐Gazally, Moaed E.; Ahmadzadeh, Behnam; Jawhar, Zanko Hassan; Siahmansouri, Homayoon

doi:10.1016/j.prp.2022.153906

Cited by 5 publications

(1 citation statement)

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“…Typical aberrations in HMGA2 function in cancer are due to overexpression, gene fusion, mutations or truncation (Fusco and Fedele, 2007; Hisaoka et al, 2002; Liu et al, 2020; Young and Narita, 2007). Aberrant HMGA2 re-expression is associated with poor tumor prognosis (Gundlach et al, 2021; Li et al, 2020; Strell et al, 2017; Thi-Hai Pham et al, 2020) and therapy resistance (Dangi-Garimella et al, 2011; Dangi-Garimella et al, 2013; Huldani et al, 2022). Functional studies demonstrated the role of HMGA2 in various aspects of neoplastic transformation (Fedele et al, 2006; Vallone et al, 1997), invasion (Thuault et al, 2006; Watanabe et al, 2009) and metastasis (Wang et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Up-regulated transcriptional regulators in mutant RAS gene signatures: a time-resolved multi-omics study in generic epithelial cell models

Kasack,

Metzger,

Koch

et al. 2024

Preprint

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The expression of mutated RAS genes drives extensive transcriptome alterations. Perturbation experiments have shown that the transcriptional responses to downstream effector pathways are partially unique and non-overlapping, suggesting a modular organization of the RAS-driven expression program. However, the relationship between individual deregulated transcription factors and the entire cancer cell-specific genetic program is poorly understood. To identify potential regulators of the RAS/MAPK-dependent fraction of the genetic program, we monitored transcriptome and proteome changes following conditional, time-resolved expression of mutant HRASG12Vin human epithelial cells during neoplastic conversion. High mobility group AT hook2 (HMGA2), an architectural chromatin modulating protein and oncofetal tumour marker, was recovered as the earliest upregulated transcription factor. Knock-down of HMGA2 reverted anchorage-independent growth and epithelial-mesenchymal transition not only in HRAS-transformed cells but also in an independent, KRASG12V-driven rat epithelial model. Moreover, HMGA2 silencing reverted the deregulated expression of 60% of RAS-responsive target genes. These features qualify HMGA2 as a master regulator of mutant RAS-driven expression patterns. The delayed deregulation of FOSL1, ZEB1 and other transcription factors with known oncogenic activity suggests that HMGA2 acts in concert with a network of regulatory factors to trigger full neoplastic conversion. Although transcription factors are considered difficult to drug, the central role of HMGA2 in the transcription factor network as well as its relevance for cancer prognosis has motivated attempts to block its function using small molecular weight compounds. The further development of direct HMGA2 antagonists may prove useful in cancer cells that have developed resistance to signalling chain inhibition.

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