Research

Tumors must adapt to fluctuating oxygen and nutrient availability as they grow, metastasize, and respond to treatment. The Zhang Lab investigates how oxygen-sensing pathways, metabolic and epigenetic programs, and protein-stability networks enable this adaptation. Our goal is to translate fundamental discoveries into therapeutic strategies for aggressive cancers, with a particular emphasis on clear cell renal cell carcinoma (ccRCC) and breast cancer.

A central focus of our research is the von Hippel–Lindau (VHL) tumor suppressor pathway. Under normal oxygen conditions, prolyl hydroxylases—including EGLN1, EGLN2, and EGLN3—modify hypoxia-inducible factors (HIFs), enabling their recognition by the VHL E3 ubiquitin ligase and subsequent degradation. Loss of VHL, a defining event in ccRCC, disrupts this process and activates HIF-dependent and HIF-independent programs that promote tumor growth, metastasis, immune evasion, and therapeutic resistance.

Our Mission

We seek to discover fundamental mechanisms of cancer development, progression, metastasis, and treatment resistance and translate these discoveries into new therapeutic opportunities. Our laboratory combines functional genomics, epigenomics, metabolomics, chemical biology, and clinically relevant cancer models to study aggressive breast and kidney cancers.

Research Themes and Achievements

1. Clear Cell Renal Cell Carcinoma

VHL-Regulated Oncogenic Programs

We investigate both HIF-dependent and HIF-independent consequences of VHL loss and the mechanisms through which these pathways regulate gene expression, metabolism, and tumor progression.

  • Identified ZHX2 as an oncogenic driver in VHL-deficient kidney cancer (Science, 2018)
  • Discovered SFMBT1 as a new oncogenic driver following VHL loss (Molecular Cell, 2020)
  • Characterized USP37-mediated deubiquitination of HIF-2α (PNAS, 2020)
  • Defined the USP13–ZHX2 protein-stability pathway in kidney cancer (PNAS, 2022)
  • Discovered that VHL controls m6A-dependent gene expression during renal tumorigenesis (Journal of Clinical Investigation, 2024)

 

Therapeutic Vulnerabilities and Targeted Protein Degradation

We use genetic and chemical screens to identify selective vulnerabilities in VHL-deficient tumors and develop therapeutic strategies for targeting these dependencies.

  • Identified TBK1 as a synthetic-lethal vulnerability in cancers with VHL loss (Cancer Discovery, 2020)
  • Discovered the DCLK2–TBK1 oncogenic signaling axis in ccRCC (Molecular Cell, 2024)
  • Demonstrated that BBOX1 restrains TBK1–mTORC1 oncogenic signaling in ccRCC (Nature Communications, 2025)
  • Developed a potent and selective TBK1 degrader that suppresses ccRCC progression (Cell Chemical Biology, 2026)

 

Cancer Metabolism

We investigate how VHL loss and hypoxia reprogram lipid, amino-acid, and mitochondrial metabolism to support kidney-cancer growth and survival.

  • Identified a JMJD6–DGAT1 signaling pathway that controls lipid-droplet formation and ccRCC tumorigenesis (Molecular Cell, 2022)
  • Defined ZNF395 as a hypoxia-responsive regulator of mitochondrial glutaminolysis in ccRCC (Cancer Research, 2026)

 

Functional Genomics and Metastasis

We apply genome-wide functional screens and multi-omics approaches to identify transcriptional enhancers, signaling pathways, and metastatic programs that sustain ccRCC.

  • Identified a cytokine–enhancer circuit that drives HIF-2α activation in renal cancer (Journal of Clinical Investigation, 2026)
  • Discovered that SWI/SNF ATPase-mediated silencing of HLF promotes lung metastasis in solid cancers (Nature Communications, 2025)

 

2. Breast Cancer

Oxygen Sensing and Metabolic Regulation

Our breast-cancer program investigates how oxygen-sensing enzymes and metabolic pathways regulate tumor growth, stem-like cancer-cell states, and resistance to therapy.

  • Defined an EGLN2–NRF1–PGC-1α pathway controlling mitochondrial function in breast cancer (EMBO Journal, 2015)
  • Identified adenylosuccinate lyase as a prolyl-hydroxylase-regulated oncogenic driver in triple-negative breast cancer (Nature Communications, 2019)
  • Identified BBOX1 as a metabolic therapeutic target in triple-negative breast cancer (Cancer Discovery, 2020)
  • Used integrated metabolic and gene-expression profiling to reveal therapeutic opportunities in rapidly proliferating breast cancers (Cancer Research, 2021)
  • Demonstrated that FDXR promotes primary and endocrine-resistant ER-positive breast-cancer growth through CPT1A-mediated fatty-acid oxidation (Frontiers in Oncology, 2023)

 

HIF Signaling and Therapeutic Resistance

We investigate how hypoxia-responsive transcriptional programs support aggressive breast cancers and how tumor-cell plasticity contributes to resistance.

  • Demonstrated that ZHX2 promotes HIF-1 oncogenic signaling in triple-negative breast cancer (eLife, 2021)
  • Demonstrated that targeting KIF20A sensitizes stem-like triple-negative breast cancer cells to standard chemotherapy (Journal of Clinical Investigation, 2025)

 

3. Protein Hydroxylation and Epigenetic Regulation

We study how oxygen-sensitive protein modifications and chromatin-regulatory mechanisms control gene expression and malignant cell states.

  • Discovered that EGLN2-mediated prolyl hydroxylation regulates FOXO3A protein stability (Genes & Development, 2014)
  • Identified histone H3 proline-16 hydroxylation as an oxygen-sensitive chromatin modification that regulates mammalian gene expression (Nature Genetics, 2022)

 

Research Environment

Our collaborative and supportive research environment is dedicated to:

  • Making rigorous and impactful discoveries in cancer biology
  • Translating scientific findings into therapeutic opportunities
  • Training the next generation of cancer scientists
  • Supporting the professional development and independence of every laboratory member