Haojie Huang, Ph.D., conducts research in gene transcription on-and-off, as it constitutes a critical mechanism in the regulation of biological processes.
Abnormal gene transcription often leads to human diseases, such as cancer. Dr. Huang's research team is primarily interested in regulation and function of biologically important transcription regulatory molecules, including transcription factors (AR and FOXO1), transcription coregulators (CBP and p300), histone-chromatin modifiers (EZH2) and upstream modulators (SPOP, a tumor suppressor highly mutated in human prostate cancer).
Dr. Huang's research focuses on regulation of the functions of transcription regulatory proteins by mechanisms such as phosphorylation, acetylation, ubiquitination and protein-protein interaction and these proteins' roles in initiation and progression of cancer, especially prostate cancer. A new direction in his lab is to investigate the biogenesis and functions of enhancer RNAs (eRNAs) and their role in cancer development and progression.
Many advanced techniques routinely utilized in the laboratory include gene knockout by transcription activator-like effector nuclease (TALEN) and clustered regularly interspaced short palindromic repeats/CRISPR-associated 9 (CRISPR/Cas9), tumor imaging in live animals, lentivirus-mediated gene silencing, chromatin immunoprecipitation (ChIP), ChIP-seq, RNA immunoprecipitation (RIP)-seq, strand-specific RNA-seq, polysome and ribosome profiling, and embryonic and cancer stem cell culture and manipulation.
- PTEN-FOXO1 tumor suppressors and prostate cancer survival and metastasis. PTEN is one of the most frequently mutated or deleted tumor suppressor genes in prostate cancer. Dr. Huang's team is interested in defining molecular mechanisms by which loss of PTEN leads to inhibition of the fork-head nuclear factor FOXO1, thereby promoting prostate cancer cell proliferation, survival, metastasis and resistance to cancer therapies.
Aberrant activation of the androgen receptor (AR) and therapy resistance in prostate cancer. Androgens and the AR play a pivotal role in prostate cancer development, and androgen deprivation therapy is the standard treatment for metastatic prostate cancer. However, the majority of prostate cancers relapse following androgen ablation. Intriguingly, the AR is still functionally active even in the presence of very low levels of androgens.
Dr. Huang is interested in defining the molecular mechanism by which the AR becomes promiscuously active during androgen refractory progression of prostate cancer and elucidating the molecular pathways promoting intratumoral androgen biosynthesis and resistance to enzalutamide and abiraterone, hormonal therapies second-generation AR inhibitors.
- Transcription coregulators in prostate tumorigenesis. These molecules are important for transcription factor-initiated gene transcription. Given that the function of transcription coregulators are often dysregulated in human prostate cancers, a gene knockout approach has been taken to investigate how loss of transcription coregulators such as CBP and p300 impacts prostate tumorigenesis and prostate cancer progression and metastasis.
- Chromatin structure, epigenetic modulation and prostate cancer progression. The Polycomb group protein EZH2 primarily acts as a chromatin-modifying enzyme that catalyzes trimethylation of lysine 27 on histone H3 (H3K27me3). This histone modification promotes formation of repressive chromatin and epigenetic silencing of a large number of tumor suppressor genes that promote cell differentiation and inhibit cell proliferation and migration or invasion, thereby implying a role of EZH2 in cancer progression. Dr. Huang's team is interested in understanding how the potent functions of EZH2 is regulated under physiological conditions and how deregulation of EZH2 under pathological scenario promotes prostate cancer growth, migration, metastasis and expansion of prostate cancer stem cell population.
- Enhancer RNAs (eRNAs) and their role in cancer. Prostate-specific antigen (PSA) is one of the strongest genes regulated by AR. Its protein has been used as a biomarker for prostate cancer diagnosis and prognosis, but its biological role in prostate cancer is not established. The noncoding RNAs — eRNAs — are a newly defined class of RNAs that do not encode protein, but still are functionally important. Dr. Huang's lab is currently investigating how eRNAs transcribed from the PSA gene enhancer (PSA eRNAs) play an essential role in regulation of AR-mediated gene expression and androgen refractory growth of castration-resistant prostate cancer cells.
- SPOP, a tumor suppressor highly mutated in human prostate cancer. The gene encoding Speckle-type POZ protein (SPOP) is the most commonly mutated tumor suppressor gene in human primary prostate cancer. Dr. Huang's lab is currently investigating how SPOP mutations promote prostate tumorigenesis, aberrant AR transcriptional activity, genomic instability and therapy resistance.
Significance to patient care
Findings from Dr. Huang lab's research will not only shed new light on the etiology of prostate cancer but also may lead to identifying novel targets for diagnostics, prognostics and therapeutics for this lethal disease.
- Regular member, Cancer Molecular Pathobiology (CAMP) Study Section, National Institute of Health, 2015-2021
- Principal investigator, Movember Foundation-Prostate Cancer Foundation Challenge Award, 2015-2017
- Associate editor, Cancer Research journal, 2016-present
- Editorial adviser, Asian Journal of Urology, 2015-present
- Member, editorial board, Cancer Letters, 2015-present
- Recipient, Young Investigator Award, the Society for Basic Urologic Research, 2006