The oncogene AAMDC links PI3K-AKT-mTOR signaling with metabolic reprograming in estrogen receptor-positive breast cancer.

Adipogenesis associated Mth938 domain containing (AAMDC) represents an uncharacterized oncogene amplified in aggressive estrogen receptor-positive breast cancers. We uncover that AAMDC regulates the expression of several metabolic enzymes involved in the one-carbon folate and methionine cycles, and lipid metabolism. We show that AAMDC controls PI3K-AKT-mTOR signaling, regulating the translation of ATF4 and MYC and modulating the transcriptional activity of AAMDC-dependent promoters.

Epigenome engineering: new technologies for precision medicine.

Chromatin adopts different configurations that are regulated by reversible covalent modifications, referred to as epigenetic marks. Epigenetic inhibitors have been approved for clinical use to restore epigenetic aberrations that result in silencing of tumor-suppressor genes, oncogene addictions, and enhancement of immune responses. However, these drugs suffer from major limitations, such as a lack of locus selectivity and potential toxicities.

Innovative Precision Gene-Editing Tools in Personalized Cancer Medicine.

The development of clustered regularly interspaced short palindromic repeats (CRISPR) has spurred a successive wave of genome-engineering following zinc finger nucleases and transcription activator-like effector nucleases, and made gene-editing a promising strategy in the prevention and treatment of genetic diseases. However, gene-editing is not widely adopted in clinics due to some technical issues that challenge its safety and efficacy, and the lack of appropriate clinical regulations allowing them to advance toward improved human health without impinging on human ethics. By systematically examining the oncological applications of gene-editing tools and critical factors challenging their medical translation, genome-editing has substantial contributions to cancer driver gene discovery, tumor cell epigenome normalization, targeted delivery, cancer animal model establishment, and cancer immunotherapy and prevention in clinics.

Waking up dormant tumor suppressor genes with zinc fingers, TALEs and the CRISPR/dCas9 system.

The aberrant epigenetic silencing of tumor suppressor genes (TSGs) plays a major role during carcinogenesis and regaining these dormant functions by engineering of sequence-specific epigenome editing tools offers a unique opportunity for targeted therapies. However, effectively normalizing the expression and regaining tumor suppressive functions of silenced TSGs by artificial transcription factors (ATFs) still remains a major challenge. Herein we describe novel combinatorial strategies for the potent reactivation of two class II TSGs, MASPIN and REPRIMO, in cell lines with varying epigenetic states, using the CRISPR/dCas9 associated system linked to a panel of effector domains (VP64, p300, VPR and SAM complex), as well as with protein-based ATFs, Zinc Fingers and TALEs.

Epigenome engineering in cancer: fairytale or a realistic path to the clinic?

Epigenetic modifications such as histone post-transcriptional modifications, DNA methylation, and non-protein-coding RNAs organize the DNA in the nucleus of eukaryotic cells and are critical for the spatio-temporal regulation of gene expression. These epigenetic modifications are reversible and precisely regulated by epigenetic enzymes. In addition to genetic mutations, epigenetic modifications are highly disrupted in cancer relative to normal tissues.