Biology subjects

Huang, D. T.

Publications and source records attributed to Huang, D. T..

3 recordsLinked to original sources

bioRxiv2025

Targeting MDM2 homodimer and heterodimer disruption with DRx-098D in TP53 wild-type and mutant cancer cells

Novel pharmacological strategies capable of inhibiting pro-oncogenic MDM2 beyond its p53-dependent functions represents an increasingly attractive therapeutic strategy to treating solid and haematological cancers that are depdendent upon MDM2/MDMX, regardless of TP53 mutational status. Utilising a novel first-in-class cell-penetrating peptide disruptor of MDM2 homo- and heterodimerisation (DRx-098D), we demonstrate the anti-proliferative effect of blocking MDM2 dimerisation against a a panel of human cancer cell lines that are TP53 wild-type, mutant or null. DRx-098D elicits its anti-cancer activity via a differentiated mechanism vs. Idasanutlin (a Phase III clinical candidate MDM2-p53 small molecule inhibitor), inducing significantly superior growth inhibition against TP53 null HCT116 cells. Our preliminary data highlight, for the first time, the potential therapeutic utility of exploiting MDM2 dimerisation in TP53 wild-type and mutant cancers.

cancer biology↗

bioRxiv2024

DTX3L ubiquitin ligase ubiquitinates single-stranded nucleic acids

Ubiquitination typically involves covalent linking of ubiquitin (Ub) to a lysine residue on a protein substrate. Recently, new facets of this process have emerged, including Ub modification of non-proteinaceous substrates like ADP-ribose by the DELTEX E3 ligase family. Here we show that the DELTEX family member DTX3L expands this non-proteinaceous substrate repertoire to include single-stranded DNA and RNA. Although the N-terminal region of DTX3L contains single-stranded nucleic acid binding domains and motifs, the minimal catalytically competent fragment comprises the C-terminal RING and DTC domains (RD). DTX3L-RD catalyses ubiquitination of the 3-end of single-stranded DNA and RNA, as well as double-stranded DNA with a 3 overhang of two or more nucleotides. This modification is reversibly cleaved by deubiquitinases. NMR and biochemical analyses reveal that the DTC domain binds single-stranded DNA and facilitates the catalysis of Ub transfer from RING-bound E2-conjugated Ub. Our study unveils the direct ubiquitination of nucleic acids by DTX3L, laying the groundwork for understanding its functional implications.

biochemistry↗

bioRxiv2022

PTEN deficiency exposes a requirement for an ARF GTPase module in integrin-dependent invasion in ovarian cancer.

Dysregulation of the PI3K/AKT pathway is a common occurrence in ovarian carcinomas. Loss of the tumour suppressor PTEN in high-grade serous ovarian carcinoma (HGSOC) is associated with a patient subgroup with poor prognosis. The cellular mechanisms of how PTEN loss contributes to HGSOC are largely unknown. We utilise long-term time-lapse imaging of HGSOC spheroids coupled to a machine learning approach to classify the phenotype of PTEN loss. PTEN deficiency does not affect proliferation but rather induces PI(3,4,5)P3-rich and -dependent membrane protrusions into the extracellular matrix (ECM), resulting in a collective invasion phenotype. We identify the small GTPase ARF6 as a crucial vulnerability upon PTEN loss. Through a functional proteomic CRISPR screen of ARF6 interactors, we identify the ARF GTPase-activating protein (GAP) AGAP1 and the ECM receptor {beta}1-integrin (ITGB1) as key ARF6 interactors regulating the PTEN loss-associated invasion phenotype. ARF6 functions to promote invasion by controlling the recycling of internalised, active {beta}1-integrin complexes to maintain invasive activity into the ECM. The expression of the ARF6-centred complex in HGSOC patients is inversely associated with outcome, allowing identification of patient groups with improved versus poor outcome. ARF6 may represent a new therapeutic vulnerability in PTEN- depleted HGSOC tumours.

cancer biology↗