Converged DNA Damage Response Renders Human Hepatocellular Carcinoma Sensitive to CDK7 Inhibition

Abstract

Hepatocellular carcinoma (HCC) is a lethal malignancy with high mortality. The inhibition of cyclin-dependent kinase 7 (CDK7) activity has shown therapeutic efficacy in HCC. However, the underlying molecular mechanisms remain elusive. Here, we show that three HCC lines, HepG2, Hep3B, and SK-Hep-1, were highly susceptible to the CDK7 inhibitor THZ1. In mouse models, THZ1 effectively reduced HepG2 tumor growth and tumor weight. THZ1 arrested cell cycle and triggered MYC-related apoptosis in HepG2. To evaluate how MYC protein levels affected THZ1-induced apoptotic cell death, we overexpressed MYC in HepG2 and found that exogenously overexpressed MYC promoted cell cycle progression and increased cells in the S phase. THZ1 drastically engendered the apoptosis of MYC-overexpressing HepG2 cells in the S and G2/M phases. Importantly, transcription-inhibition-induced apoptosis is associated with DNA damage, and exogenous MYC expression further enhanced the THZ1-induced DNA damage response in MYC-overexpressing HepG2 cells. Consistently, in the HepG2 xenografts, THZ1 treatment was associated with DNA-damage-induced cell death. Together, our data indicate that the converged effect of MYC-promoted cell cycle progression and CDK7 inhibition by THZ1 confers the hypersensitivity of HCC to DNA-damage-induced cell death. Our findings may suggest a new therapeutic strategy of THZ1 against HCC.

Disruption of CDK7 signaling leads to catastrophic chromosomal instability coupled with a loss of condensin-mediated chromatin compaction

“…Given the established roles of CDK7 in promoting cell cycle progression and its reported impact on chromosomal stability ( 24 , 25 ), we questioned whether loss of CDK7 activity may induce mitotic catastrophe. Mitotic catastrophe is an oncosuppressive mechanism ( 39 , 40 ).…”

“…SMC2 is an ATPase; thus, it may be a viable pharmacologic target for rational development of small-molecule inhibitors. Such therapies could provide a complementary approach to treat TNBC as well as other cancers where CDK7 inhibitors induce genome instability, such as the recently reported effects in SCLC and HCC ( 16 , 24 , 25 , 90 , 91 ).…”

“…The ability of CDK7i to induce CIN was further demonstrated in several models of hepatocellular carcinoma (HCC) using THZ1. In this case, CIN was proposed to result from disruption of MYC-driven cell cycle progression ( 25 ).Given the myriad of activities associated with CDK7, the mechanisms by which it prevents CIN remains unknown. Specifically, it is unclear whether the CIN that occurs in response to CDK7i is dependent upon changes in the transcription of core genes involved in DNA damage and genomic instability or if it is due to the disruption of key events during cell cycle progression.…”

Recombinant immunotoxin induces tumor intrinsic STING signaling against head and neck squamous cell carcinoma

“…To establish the control and STING-overexpressing HNSCC lines, JHU-029 cells were plated 24 h prior to viral transduction. On the day of transduction, when the cells reached approximately 50% confluence, viral transduction was performed in a 6-well plate, as we previously described 31 . Briefly, the viruses were incubated with cells in Opti-MEM™ medium (Cat.…”

“…Western blot analysis was performed as previously described 29,31 . Briefly, cells seeded in the wells of a six-well plate were treated with either vehicle or hDT806 (20 nM) for 48 h before they were collected, washed with PBS, and homogenized in RIPA lysis buffer (50 mM Tris buffer, 150 mM NaCl, 1 mM EDTA, 1% NP40, 0.5% (w/v) Sodium Deoxycholate, 0.1% (w/v) SDS and proteinase/phosphatase inhibitors).…”