Sicong Zhang, PhD

Assistant Professor, UNMC Eppley Institute for Research in Cancer and Allied Diseases
Research focus: Gene (mis)regulation in cancer

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Phone: 402-559-0961

Research

Transcription is the central process that integrates RNA synthesis, modification, and processing in response to intrinsic and extrinsic signals. It is activated by transcription factors (TFs) that bind to specific DNA elements, notably enhancers and promoters. The functions of TFs require diverse cofactors, which do not bind DNA. While TFs determine which genes are activated, it is the cofactors that define the precise transcriptional outcomes by modulating chromatin environments and coordinating RNA synthesis with processing and modifications. In this way, cofactors ultimately control the robustness of transcription and the final form of RNA molecules. Distinct gene sets regulated by the same TF often require specific cofactors or specific domains of a cofactor, which ensures highly specific transcriptional regulation and offers a unique opportunity to target cofactors to inhibit specific genes when direct targeting of TFs is not feasible.  

Cancers, arising from genetic or epigenetic alterations, are highly dependent on specific transcriptional regulators that lead to dysregulated transcriptional programs. Understanding these transcriptional dependencies provides opportunities for novel therapeutic interventions in cancer. My research aims to elucidate how TFs, cofactors, and DNA elements are co-opted to control transcriptional programs to promote cancer progression, especially in the context of drug resistance. By bridging fundamental mechanistic discoveries with translational applications, my research program will uncover new therapeutic vulnerabilities and guide the development of more effective treatments for breast cancer and GBM, with broad implications for oncology. 

My past research primarily focused on transcriptional rewiring by signaling, chromatin, and RNA modification in GBM, which is the most aggressive primary brain tumor. Its dismal prognosis is driven by glioblastoma stem cells (GSCs), which sustain highly plastic transcriptional programs that drive heterogeneity, recurrence, and therapy resistance. During my PhD, I uncovered how extracellular signals rewire transcriptional programs through signaling pathways and chromatin regulators to promote malignancy. These studies established a foundational framework connecting signaling → chromatin → transcription in GBM. Moreover, I discovered that RNA demethylase ALKBH5 maintains a transcription program required for self-renewal and proliferation in GSCs by co-transcriptionally regulating a key TF (Cancer Cell, 2017). This was one of the first studies to establish a functional role for m6A methylation in tumorigenesis and the first to show that m6A erasure occurs co-transcriptionally, regulated by an antisense lncRNA.  

My current research focuses on cofactor cooperativity and drug resistance in breast cancer. ER⁺ breast cancer accounts for over 70% of breast cancers, and a promising approach of treatment has been to target bromodomain and extra-terminal domain (BET) proteins—critical transcriptional cofactors and epigenetic readers for ER and other TFs, using BET inhibitors (BETi). These drugs were designed based on the assumption that BET proteins activate oncogenes by binding acetylated histones through their bromodomains (BDs). However, BETi have failed in clinical trials, and resistance mechanisms remained a mystery. To address this, I combined genomic analysis, CRISPR-based functional studies, biochemistry, PROTAC technology, and a novel mass spectrometry-based method I developed to profile post-initiation transcription complexes. These efforts revealed a paradigm-shifting mechanism: BRD4, a key BET protein, activates MYC transcription through BD-independent recruitment by the Mediator complex and engagement of transcriptional elongation factors (Nat. Struct. Mol. Biol, 2025). This finding overturns the central premise of BET inhibition, explains BETi failure, and opens the door to next-generation therapies that target BD-independent functions of BRD4. 

Building on my current work, I will investigate the molecular basis of BRD4’s BD-independent functions to establish new principles of BET protein activity and develop novel strategies for cancer treatment. In parallel, I will investigate how TFs/cofactors control therapy-induced senescence in breast and brain tumors and how to improve therapeutic outcomes.