Related Experiment Video

Updated: Jan 6, 2026

A 3D Organotypic Melanoma Spheroid Skin Model
08:49

A 3D Organotypic Melanoma Spheroid Skin Model

Published on: May 18, 2018

16.5K

COMMD4 Drives Skin Cutaneous Melanoma Progression by Targeting PI3K-p85 to Activate PI3K-AKT

Xiaoqiang Liu1,2, Luojia Liu2, Qiaoling Wang2

  • 1Department of Plastic Surgery, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China.

Annals of the New York Academy of Sciences
|November 24, 2025
PubMed

Insights

COMMD4 is a key driver in skin cutaneous melanoma (SKCM) progression, promoting cell growth and spread. Targeting the COMMD4-PI3K-AKT pathway with triamterene offers a new therapeutic strategy for SKCM.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Skin cutaneous melanoma (SKCM) is an aggressive cancer with poorly understood molecular mechanisms.
  • The COMMD protein family's role in SKCM oncogenesis is largely undefined.
  • Identifying novel prognostic biomarkers and therapeutic targets is crucial for improving SKCM outcomes.

Purpose of the Study:

  • To investigate the functional relevance of COMMD4 in SKCM.
  • To elucidate the molecular mechanisms by which COMMD4 regulates SKCM progression.
  • To identify potential therapeutic agents targeting the COMMD4 pathway in SKCM.

Main Methods:

  • Gene knockout (COMMD4-KO) in SKCM cells to assess proliferation, migration, and invasion in vitro.
  • Xenograft tumor growth assays in vivo to evaluate COMMD4's role in tumor suppression.
  • Analysis of cell cycle regulation (G2/M phase arrest) and epithelial-mesenchymal transition (EMT) markers.
  • Investigation of the PI3K-AKT signaling pathway activation and its interaction with COMMD4.
  • Integrative Connectivity Map analysis and functional validation to identify pharmacological inhibitors.

Main Results:

  • COMMD4 acts as a prognostic biomarker positively correlated with adverse SKCM outcomes.
  • COMMD4 knockout impaired SKCM cell proliferation, migration, invasion, and suppressed tumor growth.
  • COMMD4 disruption led to G2/M phase arrest and impeded EMT by affecting E/N cadherin.
  • COMMD4 activates PI3K-AKT signaling, driving G2/M transition and EMT; PI3K-AKT reactivation rescued oncogenic phenotypes.
  • Triamterene was identified as a pharmacological inhibitor targeting the COMMD4-PI3K-AKT axis, suppressing SKCM progression.

Conclusions:

  • The COMMD4-PI3K-AKT axis is a critical regulator of SKCM progression.
  • COMMD4 plays a significant role in driving SKCM cell proliferation, migration, invasion, and EMT.
  • Triamterene is a promising repurposed therapeutic agent for SKCM by targeting the COMMD4-PI3K-AKT pathway.
Keywords:
COMMD4PI3K‐AKTPI3K‐p85SKCMtumor progression

More Related Videos

The Three-Dimensional Human Skin Reconstruct Model: a Tool to Study Normal Skin and Melanoma Progression11:02

The Three-Dimensional Human Skin Reconstruct Model: a Tool to Study Normal Skin and Melanoma Progression

Published on: August 3, 2011

50.7K
Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells06:09

Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells

Published on: June 7, 2019

9.4K

Related Concept Videos

PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a...
5.2K
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
4.6K
The Intrinsic Apoptotic Pathway01:31

The Intrinsic Apoptotic Pathway

Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
8.1K
Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
5.0K
The JAK-STAT Signaling Pathway01:20

The JAK-STAT Signaling Pathway

Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...
11.7K
Tumor Progression02:07

Tumor Progression

Tumor progression is a phenomenon where the pre-formed tumor acquires successive mutations to become clinically more aggressive and malignant. In the 1950s, Foulds first described the stepwise progression of cancer cells through successive stages.
Colon cancer is one of the best-documented examples of tumor progression. Early mutation in the APC gene in colon cells causes a small growth on the colon wall called a polyp. With time, this polyp grows into a benign, pre-cancerous tumor. Further...
7.2K